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Arterial wall active mechanics are driven by resident smooth muscle cells, which respond to biological, chemical, and mechanical stimuli and activate their cytoskeletal machinery to generate contractile stresses. The cellular mechanoresponse is sensitive to environmental perturbations, often leading to maladaptation and disease progression. When investigated at the single cell scale, however, these perturbations do not consistently result in phenotypes observed at the tissue scale. Here, a multiscale model is introduced that translates microscale contractility signaling into a macroscale, tissue-level response. The microscale framework incorporates a biochemical signaling network along with characterization of fiber networks that govern the anisotropic mechanics of vascular tissue. By incorporating both biochemical and mechanical components, the model is more flexible and more broadly applicable to physiological and pathological conditions. The model can be applied to both cell and tissue scale systems, allowing for the analysis of in vitro, traction force microscopy and ex vivo, isometric contraction experiments in parallel. When applied to aortic explant rings and isolated smooth muscle cells, the model predicts that active contractility is not a function of stretch at intermediate strain. The model also successfully predicts cell-scale and tissue-scale contractility and matches experimentally observed behaviors, including the hypercontractile phenotype caused by chronic hyperglycemia. The connection of the microscale framework to the macroscale through the multiscale model presents a framework that can translate the wealth of information already collected at the cell scale to tissue scale phenotypes, potentially easing the development of smooth muscle cell-targeting therapeutics. [ABSTRACT FROM AUTHOR]

Previous studies have shown that ferroptosis of vascular smooth muscle cells (VSMCs) is involved in the development of aortic dissection (AD) and that histone methylation regulates this process. SP2509 acts as a specific inhibitor of lysine-specific demethylase 1 (LSD1), which governs a variety of biological processes. However, the effect of SP2509 on VSMC ferroptosis and AD remains to be elucidated. This aim of this study was to investigate the role and underlying mechanism of SP2509-mediated histone methylation on VSMC ferroptosis. Here, a mouse model of AD was established, and significantly reduced levels of H3K4me1 and H3K4me2 (target of SP2509) were found in the aortas of AD mice. In VSMCs, SP2509 treatment led to a dose-dependent increase in H3K4me2 levels. Furthermore, we found that SP2509 provided equivalent protection to ferrostatin-1 against VSMC ferroptosis, as evidenced by increased cell viability, decreased cell death and lipid peroxidation. RNA-sequencing analysis and subsequent experiments revealed that SP2509 counteracted cystine deficiency-induced response to inflammation and oxidative stress. More importantly, we demonstrated that SP2509 inhibited the expression of TFR and ferritin to reduce intracellular iron levels, thereby effectively blocking the process of ferroptosis. Therefore, our findings indicate that SP2509 protects VSMCs from multiple stimulus-induced ferroptosis by reducing intracellular iron levels, thereby preventing lipid peroxidation and cell death. These findings suggest that SP2509 may be a promising drug to alleviate AD by reducing iron deposition and VSMC ferroptosis. [Display omitted] • H3K4me1 and H3K4me2 levels were significantly reduced in mouse aortic dissection tissues. • SP2509 could inhibit CD- and IKE-induced ferroptosis by reducing inflammation and oxidative stress. • SP2509 could alleviate intracellular Fe2+ accumulation, thus preventing oxidative stress and ferroptosis. [ABSTRACT FROM AUTHOR]

Three-dimensional (3D) printing with polycarbonate (PC) plastic occurs in manufacturing settings, homes, and schools. Emissions generated during printing with PC stock and bisphenol-A (BPA), an endocrine disrupter in PC, may induce adverse health effects. Inhalation of 3D printer emissions, and changes in endocrine function may lead to cardiovascular dysfunction. The goal of this study was to determine whether there were any changes in markers of peripheral or cardiovascular dysfunction in animals exposed to PC-emissions. Male Sprague Dawley rats were exposed to PC-emissions generated by 3D printing for 1, 4, 8, 15 or 30 d. Exposure induced a reduction in the expression of the antioxidant catalase (Cat) and endothelial nitric oxide synthase (eNos). Endothelin and hypoxia-induced factor 1α transcripts increased after 30 d. Alterations in transcription were associated with elevations in immunostaining for estrogen and androgen receptors, nitrotyrosine, and vascular endothelial growth factor in cardiac arteries of PC-emission exposed animals. There was also a reduction eNOS immunostaining in cardiac arteries from rats exposed to PC-emissions. Histological analyses of heart sections revealed that exposure to PC-emissions resulted in vasoconstriction of cardiac arteries and thickening of the vascular smooth muscle wall, suggesting there was a prolonged vasoconstriction. These findings are consistent with studies showing that inhalation 3D-printer emissions affect cardiovascular function. Although BPA levels in animals were relatively low, exposure-induced changes in immunostaining for estrogen and androgen receptors in cardiac arteries suggest that changes in the action of steroid hormones may have contributed to the alterations in morphology and markers of cardiac function. [ABSTRACT FROM AUTHOR]

Fibroids are benign uterine tumors characterized by the proliferation of uterine smooth muscle cells, embedded in an abundant extracellular matrix. Their prevalence is estimated to be >50% in women aged >45 years. Fibroids represent a considerable health burden. It is time to acquire a deeper mechanistic understanding of uterine fibroid-related etiology and pathogenesis, which may help pinpoint new strategies and an individualized approach. There is a need to gather prospective data and conduct studies to compare alternative approaches and assess long-term outcomes with respect to quality of life, recurrence of symptoms (bleeding and bulk symptoms), fertility, and even complications The goal of this review was to evaluate the widely accepted pathogenesis and identify risks factors and future directions for clinical and basic research into fibroids. [ABSTRACT FROM AUTHOR]

Aim: The effects of iron on vascular calcification in rats and vascular smooth muscle cells were recently reported, but clinical studies on iron and vascular calcification are scant. We studied the associations of absolute iron deficiency, coronary artery calcification and mortality in patients with maintenance haemodialysis (MHD). Methods: Transferrin saturation (TSAT), ferritin, mean corpuscular haemoglobin (MCH) and Agatston coronary artery calcium score (CACS) were studied at baseline in MHD patients and followed up for 3 years. Cox proportional hazard analyses for mortality and linear regression analyses for CACS were performed. Results: In 306 patients, the median age was 67 (56–81) years, dialysis duration was 76 (38–142) months, and diabetes prevalence was 42.5%. Fifty‐two patients had died by 3 years. Patients with absolute iron deficiency (TSAT <20% and ferritin <100 ng/mL) (n = 102) showed significantly higher CACS (p =.0266) and C‐reactive protein (p =.0011), but a lower frequency of iron formulation administration compared with patients without absolute iron deficiency at baseline (n = 204). Absolute iron deficiency was a significant predictor for 3‐year cardiovascular (CV) mortality (hazard ratio: 2.08; p =.0466), but not for 3‐year all‐cause mortality. CACS was significant predictor for both 3‐year CV and all‐cause mortality (p <.05). Absolute iron deficiency and MCH were significant determinants of CACS (p <.05). Conclusion: MHD patients with absolute iron deficiency showed significantly higher CACS than others, and absolute iron deficiency was a significant risk factor for coronary artery calcification and 3‐year CV mortality in MHD patients, but was not a significant predictor for 3‐year all‐cause mortality. [ABSTRACT FROM AUTHOR]

The RNA-binding zinc finger protein 36 (ZFP36) family participates in numerous physiological processes including transition and differentiation through post-transcriptional regulation. ZFP36L1 is a member of the ZFP36 family. This study aimed to evaluate the role of ZFP36L1 in restenosis. We found that the expression of ZFP36L1 was inhibited in VSMC-phenotypic transformation induced by TGF-β, PDGF-BB, and FBS and also in the rat carotid injury model. In addition, we found that the overexpression of ZFP36L1 inhibited the proliferation and migration of VSMCs and promoted the expression of VSMC contractile genes; whereas ZFP36L1 interference promoted the proliferation and migration of VSMCs and suppressed the expression of contractile genes. Furthermore, the RNA binding protein immunoprecipitation and double luciferase reporter gene experiments shows that ZFP36L1 regulates the phenotypic transformation of VSMCs through the posttranscriptional regulation of KLF16. Finally, our research results in the rat carotid balloon injury animal model further confirmed that ZFP36L1 regulates the phenotypic transformation of VSMCs through the posttranscriptional regulation of KLF16 and further plays a role in vascular injury and restenosis in vivo. [Display omitted] • The expression of ZFP36L1 was inhibited in VSMC-phenotypic transformation induced by TGF-β, PDGF-BB and FBS and also in the rat carotid injury model. • Overexpression of ZFP36L1 reduces intimal hyperplasia induced by carotid balloon injury in rats. • The expression of ZFP36L1 regulates the phenotypic transformation of VSMCs. • ZFP36L1 regulates the phenotypic transformation of VSMCs by regulating the expression of KLF16 in vitro and in vivo. [ABSTRACT FROM AUTHOR]

Thoracic aortic dissection (TAD) is characterized by extracellular matrix (ECM) dysregulation. Aberrations in the ECM stiffness can lead to changes in cellular functions. However, the mechanism by which ECM softening regulates vascular smooth muscle cell (VSMCs) phenotype switching remains unclear. To understand this mechanism, we cultured VSMCs in a soft extracellular matrix and discovered that the expression of microRNA (miR)-143/145, mediated by activation of the AKT signalling pathway, decreased significantly. Furthermore, overexpression of miR-143/145 reduced BAPN-induced aortic softening, switching the VSMC synthetic phenotype and the incidence of TAD in mice. Additionally, high-throughput sequencing of immunoprecipitated RNA indicated that the TEA domain transcription factor 1 (TEAD1) is a common target gene of miR-143/145, which was subsequently verified using a luciferase reporter assay. TEAD1 is upregulated in soft ECM hydrogels in vitro, whereas the switch to a synthetic phenotype in VSMCs decreases after TEAD1 knockdown. Finally, we verified that miR-143/145 levels are associated with disease severity and prognosis in patients with thoracic aortic dissection. ECM softening, as a result of promoting the VSMCs switch to a synthetic phenotype by downregulating miR-143/145, is an early trigger of TAD and provides a therapeutic target for this fatal disease. miR-143/145 plays a role in the early detection of aortic dissection and its severity and prognosis, which can offer information for future risk stratification of patients with dissection. [Display omitted] • ECM softening down-regulates miR-143/145 expression via AKT phosphorylation. • TEAD1 as a target of miR-143/145 linking ECM softening to VSMC phenotype switching. • miR-143/145 levels correlate with TAD severity and prognosis, suggesting biomarker potential. [ABSTRACT FROM AUTHOR]

Mucus provides a protective barrier that is crucial for host defense in the lungs. However, excessive or abnormal mucus can have pathophysiological consequences in many pulmonary diseases, including asthma. Patients with asthma are treated with agents that relax airway smooth muscle and reduce airway inflammation, but responses are often inadequate. In part, this is due to the inability of existing therapeutic agents to directly target mucus. Accordingly, there is a critical need to better understand how mucus hypersecretion and airway plugging are affected by the epithelial cells that synthesize, secrete, and transport mucus components. This review highlights recent advances in the biology of mucin glycoproteins with a specific focus on MUC5AC and MUC5B, the chief macromolecular components of airway mucus. An improved mechanistic understanding of key steps in mucin production and secretion will help reveal novel potential therapeutic strategies. [ABSTRACT FROM AUTHOR]

Background Methods Key Results Conclusion & Inferences The natural history and pathophysiology of diverticular disease (DD) are still uncertain. An ex‐vivo human complicated DD (cDD) model has recently shown a predominant transmural oxidative imbalance. The present study aims to evaluate whether the previously described alterations may precede the symptomatic form of the disease.Colonic surgical samples obtained from patients with asymptomatic diverticulosis (DIV), complicated DD, and controls were systematically and detailed morphologically and molecularly analyzed. Therefore, histologic, histomorphometric, immunohistochemical evaluation, and gene and protein expression analysis were performed to characterize colonic muscle changes and evaluate chronic inflammation, oxidative imbalance, and hypoxia. Functional muscle activity was tested on strips and isolated cells in response to contractile and relaxant agents.Compared with controls, DD showed a marketed increase in muscle layer thickness, smooth muscle cell syncytium disarray, and increased interstitial fibrosis; moreover, the observed features were more evident in the cDD group. These changes mainly affected longitudinal muscle and were associated with altered contraction‐relaxation dynamics and fibrogenic switch of smooth muscle cells. Chronic lymphoplasmacytic inflammation was primarily evident in the mucosa and spared the muscle. A transmural increase in carbonylated and nitrated proteins, with loss of antioxidant molecules, characterized both stages of DD, suggesting early oxidative stress probably triggered by recurrent ischemic events, more pronounced in cDD, where HIF‐1 was detected in both muscle and mucosa.The different DD clinical scenarios are part of a progressive process, with oxidative imbalance representing a new target in the management of DD. [ABSTRACT FROM AUTHOR]

Background: Peritoneal carcinomatosis was the main reason leading to gastric cancer (GC)-related death. We aimed to explore the roles of dysregulated microRNAs (miRNAs) and related immune regulation activities in GC-associated malignant ascites. Methods: GSE126399 were downloaded from GEO database. Differentially expressed miRNAs in GC ascites samples was firstly screened, and critical miRNAs were further investigated by LASSO (least absolute shrinkage and selection operator) logistic regression and random forest (RF) algorithm. Receiver operating characteristic of critical miRNAs was also constructed. Moreover, functional analysis, immune cell infiltration associated with differentially expressed mRNAs were further analyzed. After selecting key modules by weighted gene co-expression network analysis, mRNAs related with survival performance and transcription factor (TF)-miRNA-mRNA network were constructed. Results: Hsa-miR-181b-5p was confirmed as critical differentially expressed miRNAs in GC ascites. Then, the tumor samples were divided into high- and low- expression groups divided by mean expression levels of hsa-miR-181b-5p, and subjects with high hsa-miR-181b-5p levels had better survival outcomes. In total, 197 differentially expressed mRNAs associated with hsa-miR-181b-5p levels were obtained, and these mRNAs were mainly enriched in muscle activity and vascular smooth muscle contraction. Hsa-miR-181b-5 was positively related with activated CD4 T cells and negatively related with eosinophil. 17 mRNAs were selected as mRNAs significantly related with prognosis of GC, such as PDK4 and RAMP1. Finally, 75 TF-miRNA-mRNA relationships were obtained, including 15 TFs, hsa-miR-181b-5p, and five mRNAs. Conclusion: Our data suggest that the differentially expressed hsa-miR-181b-5p in ascites samples of GC patients may be a valuable prognostic marker and a potential target for therapeutic intervention, which should be validated in the near future. [ABSTRACT FROM AUTHOR]

Abdominal aortic aneurysm (AAA) is a common vascular disease that has attracted widespread attention due to its characteristic of being asymptomatic and high mortality rate. In this study, we present a novel woven vascular stent-graft, which can improve thrombus formation resulting from excessive smooth muscle cell proliferation following blood vessel stent implantation. To achieve this, we adopted the orthogonal design method to optimize the production process parameters and then coated the surface of the woven stent with chitosan/heparin using a layer-by-layer self-assembly technique based on the electrostatic binding principle, and the performance of the stent before and after modification was comprehensively evaluated. The results demonstrated that the coating had no impact on the mechanical properties, wall thickness, and cross-sectional water permeability of the membranes. Remarkably, the release rate of heparin reached as high as 90.88% at 216 h, effectively inhibiting the growth of smooth muscle cells. In conclusion, the new woven polyester vascular stent-graft provides a potential application prospect for the treatment of AAA. [ABSTRACT FROM AUTHOR]

Stimulation of the calcium‐sensing receptor (CaSR) regulates vascular contractility, but cellular mechanisms involved remain unclear. This study investigated the role of perivascular sensory nerves in CaSR‐induced relaxations of male rat mesenteric arteries. In fluorescence studies, colocalisation between synaptophysin, a synaptic vesicle marker, and the CaSR was present in the adventitial layer of arterial segments. Using wire myography, increasing external Ca2+ concentration ([Ca2+]o) from 1 to 10 mM induced vasorelaxations, previously shown to involve the CaSR, which were inhibited by pretreatment with capsaicin. [Ca2+]o‐induced vasorelaxations were partially reduced by the calcitonin gene‐related peptide (CGRP) receptor blockers, CGRP 8–37 and BIBN 4096, and the neurokinin 1 (NK1) receptor blocker L733,060. The inhibitory effect of CGRP 8–37 required a functional endothelium whereas the inhibitory action of L733,060 did not. Complete inhibition of [Ca2+]o‐induced vasorelaxations occurred when CGRP 8–37 and L733,060 were applied together. [Ca2+]o‐induced vasorelaxations in the presence of capsaicin were abolished by the ATP‐dependent K+ channel (KATP) blocker PNU 37883, but unaffected by the endothelium nitric oxide synthase (eNOS) inhibitor L‐NAME. We suggest that the CaSR on perivascular sensory nerves mediate relaxations in rat mesenteric arteries via endothelium‐dependent and ‐independent mechanisms involving CGRP and NK1 receptor‐activated NO production and KATP channels, respectively. [ABSTRACT FROM AUTHOR]

Background: Aortic dissection (AD) is a macrovascular disease which is pathologically characterized by aortic media degeneration.This experiment aims to explore how iron deficiency (ID) affects the function of vascular smooth muscle cell (VSMC) and participates in the occurrence and development of AD by regulating gene expression. Methods: The relationship between iron and AD was proved by Western-blot (WB) and immunostaining experiments in human and animals. Transcriptomic sequencing explored the transcription factors that were altered downstream. WB, flow cytometry and immunofluorescence were used to demonstrate whether ID affected HIF1 expression through oxygen transport. HIF1 signaling pathway and phenotypic transformation indexes were detected in cell experiments. The use of the specific HIF1 inhibitor PX478 further demonstrated that ID worked by regulating HIF1. Results: The survival period of ID mice was significantly shortened and the pathological staining results were the worst. Transcriptomic sequencing indicated that HIF1 was closely related to ID and the experimental results indicated that ID might regulate HIF1 expression by affecting oxygen balance. HIF1 activation regulates the phenotypic transformation of VSMC and participates in the occurrence and development of AD in vivo and in vitro.PX478, the inhibition of HIF1, can improve ID-induced AD exacerbation. Highlights: This study demonstrated for the first time that ID can alter HIF1 transcription through oxygen transport and participate in the occurrence of AD. The promoting effect of ID on phenotypic transformation of VSMC may be through HIF1 signaling pathway. Specific inhibition of HIF1 can effectively alleviate the exacerbation of AD disease caused by ID and HIF1 may be an important target for drug therapy of AD. [ABSTRACT FROM AUTHOR]

Aortic root aneurysm is a potentially life‐threatening condition that may lead to aortic rupture and is often associated with genetic syndromes, such as Marfan syndrome (MFS). Although studies with MFS animal models have provided valuable insights into the pathogenesis of aortic root aneurysms, this understanding of the transcriptomic and epigenomic landscape in human aortic root tissue remains incomplete. This knowledge gap has impeded the development of effective targeted therapies. Here, this study performs the first integrative analysis of single‐nucleus multiomic (gene expression and chromatin accessibility) and spatial transcriptomic sequencing data of human aortic root tissue under healthy and MFS conditions. Cell‐type‐specific transcriptomic and cis‐regulatory profiles in the human aortic root are identified. Regulatory and spatial dynamics during phenotypic modulation of vascular smooth muscle cells (VSMCs), the cardinal cell type, are delineated. Moreover, candidate key regulators driving the phenotypic modulation of VSMC, such as FOXN3, TEAD1, BACH2, and BACH1, are identified. In vitro experiments demonstrate that FOXN3 functions as a novel key regulator for maintaining the contractile phenotype of human aortic VSMCs through targeting ACTA2. These findings provide novel insights into the regulatory and spatial dynamics during phenotypic modulation in the aneurysmal aortic root of humans. [ABSTRACT FROM AUTHOR]

Pulmonary hypertension (PH) is characterized by vascular remodeling predominantly driven by a phenotypic switching in pulmonary artery smooth muscle cells (PASMCs). However, the underlying mechanisms for this phenotypic alteration remain incompletely understood. Here, we identified that RNA methyltransferase METTL3 is significantly elevated in the lungs of hypoxic PH (HPH) mice and rats, as well as in the pulmonary arteries (PAs) of HPH rats. Targeted deletion of Mettl3 in smooth muscle cells exacerbated hemodynamic consequences of hypoxia-induced PH and accelerated pulmonary vascular remodeling in vivo. Additionally, the absence of METTL3 markedly induced phenotypic switching in PASMCs in vitro. Mechanistically, METTL3 depletion attenuated m6A modification and hindered the processing of pri-miR-143/145, leading to a downregulation of miR-143-3p and miR-145-5p. Inhibition of hnRNPA2B1, an m6A mediator involved in miRNA maturation, similarly resulted in a significant reduction of miR-143-3p and miR-145-5p. We demonstrated that miR-145-5p targets Krüppel-like factor 4 (KLF4) and miR-143-3p targets fascin actin-bundling protein 1 (FSCN1) in PASMCs. The decrease of miR-145-5p subsequently induced an upregulation of KLF4, which in turn suppressed miR-143/145 transcription, establishing a positive feedback circuit between KLF4 and miR-143/145. This regulatory circuit facilitates the persistent suppression of contractile marker genes, thereby sustaining PASMC phenotypic switch. Collectively, hypoxia-induced upregulation of METTL3, along with m6A mediated regulation of miR-143/145, might serve as a protective mechanism against phenotypic switch of PASMCs. Our results highlight a potential therapeutic strategy targeting m6A modified miR-143/145-KLF4 loop in the treatment of PH. [ABSTRACT FROM AUTHOR]

BACKGROUND: Atherosclerosis, a leading cause of cardiovascular disease, involves the pathological activation of various cell types, including immunocytes (eg, macrophages and T cells), smooth muscle cells (SMCs), and endothelial cells. Accumulating evidence suggests that transition of SMCs to other cell types, known as phenotypic switching, plays a central role in atherosclerosis development and complications. However, the characteristics of SMC-derived cells and the underlying mechanisms of SMC transition in disease pathogenesis remain poorly understood. Our objective is to characterize tumor cell--like behaviors of SMC-derived cells in atherosclerosis, with the ultimate goal of developing interventions targeting SMC transition for the prevention and treatment of atherosclerosis. METHODS: We used SMC lineage tracing mice and human tissues and applied a range of methods, including molecular, cellular, histological, computational, human genetics, and pharmacological approaches, to investigate the features of SMC-derived cells in atherosclerosis. RESULTS: SMC-derived cells in mouse and human atherosclerosis exhibit multiple tumor cell--like characteristics, including genomic instability, evasion of senescence, hyperproliferation, resistance to cell death, invasiveness, and activation of comprehensive cancer-associated gene regulatory networks. Specific expression of the oncogenic mutant KrasG12D in SMCs accelerates phenotypic switching and exacerbates atherosclerosis. Furthermore, we provide proof of concept that niraparib, an anticancer drug targeting DNA damage repair, attenuates atherosclerosis progression and induces regression of lesions in advanced disease in mouse models. CONCLUSIONS: Our findings demonstrate that atherosclerosis is an SMC-driven tumor-like disease, advancing our understanding of its pathogenesis and opening prospects for innovative precision molecular strategies aimed at preventing and treating atherosclerotic cardiovascular disease. [ABSTRACT FROM AUTHOR]

The article explores the concept of "Athero-Oncology," which examines the similarities between atherosclerosis and cancer. Both diseases share common risk factors and characteristics, such as DNA damage, clonal expansion, hyperproliferation, and chronic inflammation. Smooth muscle cells (SMCs) have been identified as important regulators of plaque progression and stability in atherosclerosis. Recent research suggests that SMCs in atherosclerotic plaques exhibit similarities to cancer cells, including oxidative DNA damage, genomic instability, and activation of cancer-associated signaling pathways. Understanding the role of SMCs and developing preventative and therapeutic strategies is crucial for managing atherosclerosis. A new study found that DNA damage and tumor cell-like features play a significant role in the development of atherosclerosis. The study discovered that DNA damage and sequence variations in SMCs within plaques can lead to the proliferation and migration of these cells, contributing to plaque formation. The study also found that an anticancer drug called niraparib, which inhibits DNA damage repair, can reduce the development and regression of atherosclerosis. However, more research is needed to develop effective therapies for atherosclerosis, as these drugs can have adverse effects. Understanding the similarities and differences between SMCs in atherosclerosis and true tumor cells may provide valuable insights for both diseases. [Extracted from the article]

Airway remodelling in lung diseases can be treated by inhibiting excessive smooth muscle cell proliferation. Zedoarondiol (Zed) is a natural compound isolated from the Chinese herb Curcuma longa. The caveolin-1 (CAV-1) is widely expressed in lung cells and plays a key role in platelet-derived growth factor (PDGF) signalling and cell proliferation. This study aims to investigate the effect of Zed on human bronchial smooth muscle cell (HBSMC) proliferation and explore its potential molecular mechanisms. We assessed the effect of Zed on the proliferation of PDGF-stimulated HBSMCs and performed proteomic analysis to identify potential molecular targets and pathways. CAV1 siRNA was used to validate our findings in vitro. In PDGF-stimulated HBSMCs, Zed significantly inhibited excessive proliferation of HBSMCs. Proteomic analysis of zedoarondiol-treated HBSMCs revealed significant enrichment of differentially expressed proteins in cell proliferation-related pathways and biological processes. Zed inhibition of HBSMC proliferation was associated with upregulation of CAV1, regulation of the CAV-1/PDGF pathway and inhibition of MAPK and PI3K/AKT signalling pathway activation. Treatment of HBSMCs with CAV1 siRNA partly reversed the inhibitory effect of Zed on HBSMC proliferation. Thus, this study reveals that zedoarondiol potently inhibits HBSMC proliferation by upregulating CAV-1 expression, highlighting its potential value in airway remodelling and related diseases. [ABSTRACT FROM AUTHOR]

Cerebral amyloid angiopathy is characterized by a weakening of the small- and medium-sized cerebral arteries, as their smooth muscle cells are progressively replaced with acellular amyloid β, increasing vessel fragility and vulnerability to microhemorrhage. In this context, an aberrant overactivation of the complement system would further aggravate this process. The surface protein CD59 protects most cells from complement-induced cytotoxicity, but expression levels can fluctuate due to disease and varying cell types. The degree to which CD59 protects human cerebral vascular smooth muscle (HCSM) cells from complement-induced cytotoxicity has not yet been determined. To address this shortcoming, we selectively blocked the activity of HCSM-expressed CD59 with an antibody, and challenged the cells with complement, then measured cellular viability. Unblocked HCSM cells proved resistant to all tested concentrations of complement, and this resistance decreased progressively with increasing concentrations of anti-CD59 antibody. Complete CD59 blockage, however, did not result in a total loss of cellular viability, suggesting that additional factors may have some protective functions. Taken together, this implies that CD59 plays a predominant role in HCSM cellular protection against complement-induced cytotoxicity. The overexpression of CD59 could be an effective means of protecting these cells from excessive complement system activity, with consequent reductions in the incidence of microhemorrhage. The precise extent to which cellular repair mechanisms and other complement repair proteins contribute to this resistance has yet to be fully elucidated. [ABSTRACT FROM AUTHOR]

Stretch-activated two-pore domain K+ (K2P) channels play important roles in many visceral organs, including the urinary bladder. The TWIK-related K+ channel TREK-1 is the predominantly expressed K2P channel in the urinary bladder of humans and rodents. Downregulation of TREK-1 channels was observed in the urinary bladder of patients with detrusor overactivity, suggesting their involvement in the pathogenesis of voiding dysfunction. This study aimed to characterize the long-term effects of TREK-1 on bladder function with global and smooth muscle-specific TREK-1 knockout (KO) mice. Bladder morphology, bladder smooth muscle (BSM) contractility, and voiding patterns were evaluated up to 12 mo of age. Both sexes were included in this study to probe the potential sex differences. Smooth muscle-specific TREK-1 KO mice were used to distinguish the effects of TREK-1 downregulation in BSM from the neural pathways involved in the control of bladder contraction and relaxation. TREK-1 KO mice developed enlarged urinary bladders (by 60.0% for males and by 45.1% for females at 6 mo; P < 0.001 compared with the age-matched control group) and had a significantly increased bladder capacity (by 137.7% at 12 mo; P < 0.0001) and compliance (by 73.4% at 12 mo; P < 0.0001). Bladder strips isolated from TREK-1 KO mice exhibited decreased contractility (peak force after KCl at 6 mo was 1.6 ± 0.7 N/g compared with 3.4 ± 2.0 N/g in the control group; P = 0.0005). The lack of TREK-1 channels exclusively in BSM did not replicate the bladder phenotype observed in TREK-1 KO mice, suggesting a strong neurogenic origin of TREK-1-related bladder dysfunction. NEW & NOTEWORTHY: This study compared voiding function and bladder phenotypes in global and smooth muscle-specific TREK-1 KO mice. We found significant age-related changes in bladder contractility, suggesting that the lack of TREK-1 channel activity might contribute to age-related changes in bladder smooth muscle physiology. [ABSTRACT FROM AUTHOR]

Background: Erectile dysfunction (ED), defined as the inability to achieve or maintain a penile erection sufficient to satisfy sexual behavior, is prevalent worldwide. Aim: Using previous research, bioinformatics, and experimental confirmation, we aimed to discover genes that contribute to ED through regulating hypoxia in corpus cavernosum smooth muscle cells (CCSMCs). Methods: We used the Gene Expression Omnibus to acquire the sequencing data of the corpus cavernosum transcriptome for diabetic ED and nerve injury type ED rats. We intersected the common differentially expressed genes. Further verification was performed using single cell sequencing. Real-time quantitative polymerase chain reaction and immunofluorescence were used to investigate whether the differentially expressed genes are found in the corpus cavernosum. We used induced hypoxia to assess cell viability changes, and we developed a lentivirus overexpressing Cldn4 for in vitro and in vivo experiments to measure changes in JNK signaling, fibrosis, hypoxia, and erectile function. Outcomes: Our results indicate that targeting the JNK pathway and decreasing local hypoxia may be better options for therapeutic intervention to improve erectile function. Results: We identified Cldn4 and found its expression increased in the corpora cavernosa of the 2 datasets. In addition, we found that hypoxia can increase the expression of Cldn4, activate the JNK signaling pathway, and exacerbate fibrosis in CCSMCs. Cldn4 overexpression in CCSMCs activated the JNK signaling pathway and increased fibrotic protein expression. Last, rat corpus cavernosum overexpressing Cldn4 activated the JNK signaling pathway, increased local fibrosis, and impaired erectile function. Clinical Implications: Through bioinformatics and in vitro and in vivo experiments, we found that Cldn4 has a negative effect on ED, and targeting Cldn4 may provide new ideas for ED treatment. Strengths and Limitations: Although we have identified Cldn4 as a potential target for ED treatment, we have only conducted preliminary validation on CCMSCs, and we still need to further validate in other cell lines. Conclusion: CCSMC hypoxia leads to increased Cldn4, in both nerve injury and diabetic ED rat models, and promotes fibrosis by activating the JNK signaling pathway. [ABSTRACT FROM AUTHOR]

Objective: Urinary bladder dysfunction, that is one of the most common diabetic complications, is associated with bladder overactivity, increased bladder capacity and also impaired bladder smooth muscle contractions. The involvement of hydrogen sulfide (H2S) in pathological disorders such as diabetes mellitus has been suggested. NaHS-treatment can distinctly reduce high glucose-induce cytotoxicity and oxidative stress. Reactive oxygen species are produced in increased concentrations in diabetes and may cause tissue damage, thus impaired smooth muscle function. The aim of the study was to investigate the role of H2S and reactive oxygen scavenger (ROS) on carbachol-induced detrusor smooth muscle contractions under high glucose conditions. Materials and Methods: Cumulative (10 nM-30 µM) carbachol contraction responses were obtained in bladder detrusor smooth muscle strips isolated from male New Zealand albino rabbits bladder in control group and in high glucose conditions (30 min incubation in Krebs' Henseleit solution with high glucose). Responses were repeated in the presence of sodium hydrosulfide (NaHS), catalase, superoxide dismutase (SOD) and their combinations. Contractions were expressed as a percentage of 80 mM K+ response and p<0.05 was accepted as statistically significant. Results: Cumulative contractile responses were elicited with carbachol in control group and these responses were significantly increased in the presence of high glucose. Increased carbachol contractile responses in high glucose were significantly reduced in the presence of catalase, SOD and NaHS. Conclusion: Depending on these results we may propose that H2S donors and ROS scavengers have probable benefits in treating diabetic complications such as urinary bladder dysfunction. [ABSTRACT FROM AUTHOR]

Background: Pravastatin is an oral lipid‐lowering drug, commonly used by patients with diabetes that is positively correlated with the occurrence of vascular calcification (VC), but the mechanism is unclear. Methods: In this study, 16S rRNA sequencing and qRT‐PCR wereused to detect the differential gut bacteria. Metabolomics and ELISA were used to analyze the differential metabolites. qRT‐PCR and western blotting (WB) were used to detect genes expression. Flow cytometry was used to analyze macrophage phenotype. Immunohistochemistry was used to analyze aortic calcification. Results: We found that gut Bacteroides fragilis (BF) increased significantly in patients who took pravastatin or type 2 diabetes (T2D) mice treated with pravastatin. In vitro experiments showed that pravastatin had little effect on BF but significantly promoted BF proliferation in vivo. Further analysis showed that ArsR was an important gene for pravastatin to regulate the activation of BF, and overexpression of ArsR significantly promoted the secretion of 3,4,5‐trimethoxycinnamic acid (TMCA). Importantly, pravastatin significantly promoted BF secretion of TMCA and significantly increased TMCA secretion in T2D patients or T2D mice. TMCA had little effect on vascular smooth muscle cell calcification but significantly promoted macrophage M1 polarization, which we had demonstrated that M1 macrophages promoted T2D VC. In vivo studies found that pravastatin significantly upregulated TMCA levels in the feces and serum of T2D mice transplanted with BF and promoted the macrophage M1 polarization in bone marrow and the osteoblastic differentiation of aortic cells. Similar results were obtained in T2D mice after intravenous infusion of TMCA. Conclusions: Promoting intestinal BF to secrete TMCA, which leads to macrophage M1 polarization, is an important mechanism by which pravastatin promotes calcification, and the result will be used for the optimization of clinical medication strategies of pravastatin supplying a theoretical basis and experimental basis. [ABSTRACT FROM AUTHOR]

A chemical investigation of Anthriscus sylvestris roots led to the isolation and characterization of two new nitrogen-containing phenylpropanoids (1–2) and two new phenol glycosides (8–9), along with fifteen known analogues. Structure elucidation was based on HRESIMS, 1D and 2D NMR spectroscopy, and electronic circular dichroism (ECD). In addition, compounds 3, 6, 9–10, 12, and 17 exhibited inhibitory effects against the abnormal proliferation of pulmonary arterial smooth muscle cells with IC50 values ranging from 10.7 ± 0.6 to 57.1 ± 1.1 μM. [ABSTRACT FROM AUTHOR]

Objectives: To elucidate the male urethral muscular structure and its relationship with the anorectal canal muscles, as establishing an anatomical foundation for urethral function will contribute to the prevention, diagnosis, and treatment of urinary incontinence. Methods: Eight male cadavers were used. Using a multifaceted approach, we performed macroscopic anatomical examination, histological analysis of wide‐range serial sectioning and immunostaining, and three‐dimensional (3D) reconstruction from histological sections. In the macroscopic anatomical examination, pelvic halves were meticulously dissected in layers from the medial aspect. In the histological analysis, the tissue, including the urethra and anorectal canal, was serially sectioned in the horizontal plane. The muscular structures were reconstructed and visualised in 3D. Results: The membranous portion of the urethra had three muscle layers: the longitudinal and circular muscles (smooth muscle) and the external urethral sphincter (skeletal muscle). The circular muscle was connected posteriorly to the longitudinal rectal muscle. The external urethral sphincter had a horseshoe shape, with its posterior ends continuing to the external anal sphincter, forming a 3D ring‐like sphincter. Conclusion: This study revealed skeletal and smooth muscle connections between the male urethra and anorectal canal, enabling urethral compression and closure. These anatomical muscle connections suggest a functional linkage between them. [ABSTRACT FROM AUTHOR]

Retraction: [PKC‐delta and PKD activate MAPK signal pathway in mechano‐transcription of colonic smooth muscle cells, Z. Yang, K. He, T. Wang, et al. Neurogastroenterology & Motility 2023; e14623 (https://onlinelibrary.wiley.com/doi/full/10.1111/nmo.14623)]. The above article, published online on June 6, 2023 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the authors, the Journal Editor in Chief, Maura Corsetti, and John Wiley & Sons Ltd. The retraction has been agreed due to unat[1]tributed overlap between this article and the abstract published in Gastroenterology: Li F, Sarna SK and Shi XP. Roles of PKCs and PKD in Mechanotranscription in Colonic Smooth Muscle Cells: Inhibition of Mechanotranscription as a Potential Treatment for Motility Dysfunction in Obstructive Disorders. In: 2012 Digestive Disease Week Abstract Supplement; May 19–22, San Diego, CA. Abstract 120 (https://www.gastrojournal.org/article/S0016-5085(12)60115-2/pdf) [ABSTRACT FROM AUTHOR]

Atherosclerosis (AS) is a significant contributor to cardio-cerebrovascular ischemia diseases, resulting in high mortality rates worldwide. During AS, vascular smooth muscle cells (VSMCs) play a crucial role in plaque formation by undergoing phenotypic and osteogenic switching. Long noncoding RNA nuclear paraspeckle assembly transcript 1 (NEAT1) has previously been identified as a nuclear regulator that promotes tumorigenesis and metastasis, but its role in regulating VSMCs in AS remains unclear. Our study aimed to investigate the biological functions and specific mechanisms of NEAT1 in regulating VSMCs in AS. We found that NEAT1 was upregulated in the aortas of AS mouse models and dedifferentiated primary VSMCs. Silencing NEAT1 in vitro attenuated the proliferation, migration, and osteogenic differentiation of VSMCs, while NEAT1 overexpression had the opposite effect. Furthermore, NEAT1 promoted VSMC osteogenic differentiation and vascular calcification in both in vivo and in vitro vascular calcification models. We also discovered that NEAT1 directly activates enhancer of zeste homolog 2 (EZH2), an epigenetic enzyme that suppresses the expression of senescence- and antimigration-related genes, by translocating it into the nucleus. CUT&Tag assay revealed that NEAT1 guides EZH2 to the promoters of senescence-related genes (P16, P21, and TIMP3), methylating local histones to reduce their transcription. Our findings suggest that NEAT1 functions in AS by modulating the epigenetic function of EZH2, which enhances the proliferation, migration, and osteogenic differentiation of VSMCs. This study provides new insights into the molecular mechanisms underlying the pathogenesis of AS and highlights the potential of NEAT1 as a therapeutic target of AS. NEW & NOTEWORTHY: Our study demonstrates that the upregulation of long noncoding RNA nuclear paraspeckle assembly transcript 1 (NEAT1) promotes proliferation and migration during phenotypic switching of vascular smooth muscle cells in atherosclerosis. We also provide in vivo and in vitro evidence that NEAT1 accelerates vascular calcification. Our findings identified the direct interaction between enhancer of zeste homolog 2 (EZH2) and NEAT1 during atherosclerosis. NEAT1 is necessary for EZH2 to translocate from the cytoplasm to the nucleus, where EZH2 epigenetically inhibits the expression of genes related to senescence and antimigration. [ABSTRACT FROM AUTHOR]

NOTCH3 receptor signaling has been linked to the regulation of smooth muscle cell proliferation and the maintenance of smooth muscle cells in an undifferentiated state. Pulmonary arterial hypertension (World Health Organization Group 1 idiopathic disease: PAH) is a fatal disease characterized clinically by elevated pulmonary vascular resistance caused by extensive vascular smooth muscle cell proliferation, perivascular inflammation, and asymmetric neointimal hyperplasia in precapillary pulmonary arteries. In this review, a detailed overview of the specific role of NOTCH3 signaling in PAH, including its mechanisms of activation by a select ligand, downstream signaling effectors, and physiologic effects within the pulmonary vascular tree, is provided. Animal models showing the importance of the NOTCH3 pathway in clinical PAH will be discussed. New drugs and biologics that inhibit NOTCH3 signaling and reverse this deadly disease are highlighted. [ABSTRACT FROM AUTHOR]

Vascular calcification has a global health impact that is closely linked to bone loss. The Receptor Activator of Nuclear Factor Kappa B (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) system, fundamental for bone metabolism, also plays an important role in vascular calcification. The Leucine-rich repeat-containing G-protein-coupled receptor 4 (LGR4), a novel receptor for RANKL, regulates bone remodeling, and it appears to be involved in vascular calcification. Besides RANKL, LGR4 interacts with R-spondins (RSPOs), which are known for their roles in bone but are less understood in vascular calcification. Studies were conducted in rats with chronic renal failure fed normal or high phosphorus diets for 18 weeks, with and without control of circulating parathormone (PTH) levels, resulting in different degrees of aortic calcification. Additionally, vascular smooth muscle cells (VSMCs) were cultured under non-calcifying (1 mM phosphate) and calcifying (3 mM phosphate) media with different concentrations of PTH. To explore the role of RANKL in VSMC calcification, increasing concentrations of soluble RANKL were added to non-calcifying and calcifying media. The effects mediated by RANKL binding to its receptor LGR4 were investigated by silencing the LGR4 receptor in VSMCs. Furthermore, the gene expression of the RANK/RANKL/OPG system and the ligands of LGR4 was assessed in human epigastric arteries obtained from kidney transplant recipients with calcification scores (Kauppila Index). Increased aortic calcium in rats coincided with elevated systolic blood pressure, upregulated Lgr4 and Rankl gene expression, downregulated Opg gene expression, and higher serum RANKL/OPG ratio without changes in Rspos gene expression. Elevated phosphate in vitro increased calcium content and expression of Rankl and Lgr4 while reducing Opg. Elevated PTH in the presence of high phosphate exacerbated the increase in calcium content. No changes in Rspos were observed under the conditions employed. The addition of soluble RANKL to VSMCs induced genotypic differentiation and calcification, partly prevented by LGR4 silencing. In the epigastric arteries of individuals presenting vascular calcification, the gene expression of RANKL was higher. While RSPOs show minimal impact on VSMC calcification, RANKL, interacting with LGR4, drives osteogenic differentiation in VSMCs, unveiling a novel mechanism beyond RANKL-RANK binding. [ABSTRACT FROM AUTHOR]

Cardiovascular diseases, particularly those involving arterial stenosis and smooth muscle cell proliferation, pose significant health risks. This study aimed to investigate the therapeutic potential of curcumol in inhibiting platelet‐derived growth factor‐BB (PDGF‐BB)‐induced human aortic smooth muscle cell (HASMC) proliferation, migration and autophagy. Using cell viability assays, 5‐ethynyl‐2′‐deoxyuridine (EdU) incorporation assays and Western Blot analyses, we observed that curcumol effectively attenuated PDGF‐BB‐induced HASMC proliferation and migration in a concentration‐dependent manner. Furthermore, curcumol mitigated PDGF‐BB‐induced autophagy, as evidenced by the downregulation of LC3‐II/LC3‐I ratio and upregulation of P62. In vivo experiments using an arteriosclerosis obliterans model demonstrated that curcumol treatment significantly ameliorated arterial morphology and reduced stenosis. Additionally, curcumol inhibited the activity of the KLF5/COX2 axis, a key pathway in vascular diseases. These findings suggest that curcumol has the potential to serve as a multi‐target therapeutic agent for vascular diseases. [ABSTRACT FROM AUTHOR]

Background and Purpose: Decreased aortic compliance is a precursor to numerous cardiovascular diseases. Compliance is regulated by the rigidity of the aortic wall and the vascular smooth muscle cells (VSMCs). Extracellular matrix stiffening, observed during ageing, reduces compliance. In response to increased rigidity, VSMCs generate enhanced contractile forces that result in VSMC stiffening and a further reduction in compliance. Mechanisms driving VSMC response to matrix rigidity remain poorly defined. Experimental Approach: Human aortic‐VSMCs were seeded onto polyacrylamide hydrogels whose rigidity mimicked either healthy (12 kPa) or aged/diseased (72 kPa) aortae. VSMCs were treated with pharmacological agents prior to agonist stimulation to identify regulators of VSMC volume regulation. Key Results: On pliable matrices, VSMCs contracted and decreased in cell area. Meanwhile, on rigid matrices VSMCs displayed a hypertrophic‐like response, increasing in area and volume. Piezo1 activation stimulated increased VSMC volume by promoting calcium ion influx and subsequent activation of PKC and aquaporin‐1. Pharmacological blockade of this pathway prevented the enhanced VSMC volume response on rigid matrices whilst maintaining contractility on pliable matrices. Importantly, both piezo1 and aquaporin‐1 gene expression were up‐regulated during VSMC phenotypic modulation in atherosclerosis and after carotid ligation. Conclusions and Implications: In response to extracellular matrix rigidity, VSMC volume is increased by a piezo1/PKC/aquaporin‐1 mediated pathway. Pharmacological targeting of this pathway specifically blocks the matrix rigidity enhanced VSMC volume response, leaving VSMC contractility on healthy mimicking matrices intact. Importantly, upregulation of both piezo1 and aquaporin‐1 gene expression is observed in disease relevant VSMC phenotypes. [ABSTRACT FROM AUTHOR]

[Display omitted] • CircRNA hsa_circ_0001402 inhibits VSMC proliferation and migration, while activating VSMC autophagy, thereby alleviating neointimal hyperplasia. • MiR-183-5p decreases FKBPL levels by targeting the coding sequence of FKBPL , promoting VSMC proliferation and migration, thereby exacerbating neointimal hyperplasia. • MiR-183-5p reduces BECN1 levels by targeting the 3′-untranslated region of BECN1 , inhibiting VSMC autophagy, thus exacerbating neointimal hyperplasia. • Hsa_circ_0001402 acts as a sponge for miR-183-5p. Vascular neointimal hyperplasia, a pathological process observed in cardiovascular diseases such as atherosclerosis and pulmonary hypertension, involves the abundant presence of vascular smooth muscle cells (VSMCs). The proliferation, migration, and autophagy of VSMCs are associated with the development of neointimal lesions. Circular RNAs (circRNAs) play critical roles in regulating VSMC proliferation and migration, thereby participating in neointimal hyperplasia. However, the regulatory roles of circRNAs in VSMC autophagy remain unclear. We aimed to identify circRNAs that are involved in VSMC autophagy-mediated neointimal hyperplasia, as well as elucidate the underlying mechanisms. Dual-luciferase reporter gene assay was performed to validate two competing endogenous RNA axes, hsa_circ_0001402 /miR-183-5p/FKBP prolyl isomerase like (FKBPL) and hsa_circ_0001402 /miR-183-5p/beclin 1 (BECN1). Cell proliferation and migration analyses were employed to investigate the effects of hsa_circ_0001402 , miR-183-5p, or FKBPL on VSMC proliferation and migration. Cell autophagy analysis was conducted to reveal the role of hsa_circ_0001402 or miR-183-5p on VSMC autophagy. The role of hsa_circ_0001402 or miR-183-5p on neointimal hyperplasia was evaluated using a mouse model of common carotid artery ligation. Hsa_circ_0001402 acted as a sponge for miR-183-5p, leading to the suppression of miR-183-5p expression. Through direct interaction with the coding sequence (CDS) of FKBPL , miR-183-5p promoted VSMC proliferation and migration by decreasing FKBPL levels. Besides, miR-183-5p reduced BECN1 levels by targeting the 3′-untranslated region (UTR) of BECN1 , thus inhibiting VSMC autophagy. By acting as a miR-183-5p sponge, overexpression of hsa_circ_0001402 increased FKBPL levels to inhibit VSMC proliferation and migration, while simultaneously elevating BECN1 levels to activate VSMC autophagy, thereby alleviating neointimal hyperplasia. Hsa_circ_0001402 , acting as a miR-183-5p sponge, increases FKBPL levels to inhibit VSMC proliferation and migration, while enhancing BECN1 levels to activate VSMC autophagy, thus alleviating neointimal hyperplasia. The hsa_circ_0001402 /miR-183-5p/ FKBPL axis and hsa_circ_0001402 /miR-183-5p/ BECN1 axis may offer potential therapeutic targets for neointimal hyperplasia. [ABSTRACT FROM AUTHOR]

Background: Asthma is a respiratory disease characterized by airway remodeling. We aimed to find out the role and mechanism of lncRNA MEG3 in asthma. Methods: We established a cellular model of asthma by inducing human airway smooth muscle cells (HASMCs) with PDGF-BB, and detected levels of lncRNA MEG3, miR-143-3p and FGF9 in HASMCs through qRT-PCR. The functions of lncRNA MEG3 or miR-143-3p on HASMCs were explored by cell transfection. The binding sites of miR-143-3p and FGF9 were subsequently analyzed with bioinformatics software, and validated with dual-luciferase reporter assay. MTT, 5-Ethynyl-2'-deoxyuridine (EdU) assay, and Transwell were used to detect the effects of lncRNA MEG3 or miR-143-3p on proliferation and migration of HASMCs. QRT-PCR and western blot assay were used to evaluate the level of proliferation-related marker PCNA in HASMCs. Results: The study found that lncRNA MEG3 negatively correlated with miR-143-3p, and miR-143-3p could directly target with FGF9. Silence of lncRNA MEG3 can suppress migration and proliferation of PDGF-BB-induced HASMCs via increasing miR-143-3p. Further mechanistic studies revealed that miR-143-3p negatively regulated FGF9 expression in HASMCs. MiR-143-3p could inhibit PDGF-BB-induced HASMCs migration and proliferation through downregulating FGF9. Conclusion: LncRNA MEG3 silencing could inhibit the migration and proliferation of HASMCs through regulating miR-143-3p/FGF9 signaling axis. These results imply that lncRNA MEG3 plays a protective role against asthma. [ABSTRACT FROM AUTHOR]

Objective To explore the pathological features of lung tissue in mild chronic obstructive pulmonary disease (COPD) and their association with inflammatory factors. Methods A total of 70 patients who underwent surgery for small lung nodule were prospectively included, and were divided into the normal group (n=10), the mild COPD group (n=50) and the moderate and severe COPD group (n=10). The pathological changes of lung tissue were evaluated after HE, Masson and EVG staining. The expression levels of SMA, Actin and CD31 proteins were detected by immunohistochemistry staining. Tumor necrosis factor α (TNF-α), interleukin-10 (IL-10) protein and mRNA levels were detected by immunohistochemistry and qPCR. Results Pulmonary tissue in mild COPD showed widening of alveolar septum, dilation of small airways, mild thickening of blood vessel wall and inflammatory reaction dominated by lymphocyte infiltration. Immunohistochemistry staining showed that contents of SMA and Actin proteins in mild COPD lung tissue were higher than those in the normal group (P＜0.05). In addition, the TNF- α mRNA and the positive rate of TNF- α in lung tissue of mild COPD were significantly higher than those in the normal group, while the IL-10 mRNA was significantly lower than that of the normal group (all P＜0.05). SMA and Actin were positively correlated with the positive expression of inflammatory cytokine TNF-α, but negatively correlated with the positive expression of IL-10 (all P＜0.05). Conclusion The main pathological changes of lung tissue in mild COPD include small lung blood vessel remodeling ocharacterized by thickening of small blood vessel smooth muscle layer and lymphocyte-dominated inflammatory response, while the increase of pro-inflammatory factor TNF-α and decrease of anti-inflammatory factor IL-10 are associated with pathological changes of COPD. [ABSTRACT FROM AUTHOR]

Nitric oxide (NO) plays an important role as a signalling molecule in the biological system. Organoselenium-coated or grafted biomaterials have the potential to achieve controlled NO release as they can catalyse decomposition of endogenous S-nitrosothiols to NO. However, such biomaterials are often challenged by the loss of the catalytic sites, which can affect the stability in tissue repair applications. In this work, we prepare a diselenide-containing poly(ester urethane)urea (SePEUU) polymer with Se–Se in the backbone, which is further electrospun into fibrous membranes by blending with poly(ester urethane)urea (PEUU) without diselenide bonds. The presence of catalytic sites in the main chain demonstrates stable and long-lasting NO catalytic activity, while the porous structure of the fibrous membranes ensures uniform distribution of the catalytic sites and better contact with the donor-containing solution. PEUU/SePEUU50 in 50/50 mass ratio has a physiologically adapted rate of NO release, with a sustained generation of NO after exposure to PBS at 37 °C for 30 d. PEUU/SePEUU50 has a low hemolysis and protein adsorption, with mechanical properties in the wet state matching those of natural vascular tissues. It can promote the adhesion and proliferation of human umbilical vein endothelial cells in vitro and control the proliferation of vascular smooth muscle cells in the presence of NO generation. This study exhibits the electrospun fibrous membranes have potential for utilizing as hemocompatible biomaterials for regeneration of blood-contacting tissues. Electrospun membranes of diselenide-containing poly(ester urethane)urea exhibit stable catalytic activity of NO generation, which promotes human umbilical vein endothelial cell proliferation and control the proliferation of vascular smooth muscle cells for potential applications as blood-contacting biomaterials. [ABSTRACT FROM AUTHOR]

Vascular calcification, a major risk factor for cardiovascular events, is associated with a poor prognosis in chronic kidney disease (CKD) patients. This process is often associated with the transformation of vascular smooth muscle cells (VSMCs) into cells with osteoblast-like characteristics. Damage-associated molecular patterns (DAMPs), such as extracellular histones released from damaged or dying cells, are suspected to accumulate at calcification sites. To investigate the potential involvement of DAMPs in vascular calcification, we assessed the impact of externally added histones (extracellular histones) on calcium and inorganic phosphate-induced calcification in mouse VSMCs. Our study found that extracellular histones intensified calcification. We also observed that the histones decreased the expression of VSMC marker genes while simultaneously increasing the expression of osteoblast marker genes. Additionally, histones treated with DNase I, which degrades dsDNA, attenuated this calcification, compared with the non-treated histones, suggesting a potential involvement of dsDNA in this process. Elevated levels of dsDNA were also detected in the serum of CKD model mice, underlining its potential role in vascular calcification in CKD. Our findings suggest that extracellular histones could play a pivotal role in the vascular calcification observed in CKD. [ABSTRACT FROM AUTHOR]

The striped acorn barnacle, Amphibalanus amphitrite, a taxon of Balanidae, is commonly found along Thailand's coastline. In this study, we used histological methods to describe the microscopic anatomy of A. amphitrite. All samples (n = 30) were obtained from the seagrass beds of Libong Island, Thailand, in the Andaman Sea. Histological observation of various longitudinal sections from specimens of A. amphitrite provides clear insights into the organization of organ systems in the species. The digestive tract was observed to be mainly divided into four subregions, including the cuticle‐lined mouth and esophagus, which is characterized by a high columnar epithelium, the stomach, and the intestine. The accessory organ, including the digestive gland, exhibited lobulated structures and was covered with low columnar epithelial cells on a thin layer of smooth muscle. Furthermore, we examined the reproductive system, including both the ovary and testes, as well as the process of gametogenesis. Testicular development was predominantly observed during active breeding seasons throughout the observation. [ABSTRACT FROM AUTHOR]

Lymphangioleiomyomatosis(LAM) is a slow progressive, rare cystic lung disease in women of reproductive age, associated with infiltration of the lung by atypical smooth muscle like cells, leading to the cystic destruction of the lung parenchyma. As LAM exclusively affects women of childbearing age, it can arise or exacerbate during pregnancy. Many patients with LAM are discouraged from pregnancy, although there is not much objective evidence effect on fertility. Patients diagnosed with LAM during pregnancy experience worse outcomes, so the safety of pregnancy is a vexing problem. What was worse, treatment strategies are limited on the effects of LAM on pregnancy outcomes. Pregnancy could be considered in LAM patients. Successful delivery in women with LAM depends on the condition of the LAM, which is in turn dependent on obstetricians and respiratory physicians. In this review, we describe the epidemiology, pathogenesis, diagnosis, clinical features and the treatment strategies of LAM during pregnancy. [ABSTRACT FROM AUTHOR]

Nuclear protein in testis (NUT) carcinoma, molecularly defined by the NUTM1 gene rearrangement, is most commonly reported in young adults in the sinonasal tract, nasopharynx, or thorax. At these sites, NUT carcinoma is an extremely aggressive malignancy with dismal prognosis. Recently, five cases of primary cutaneous NUT adnexal carcinoma have been reported with BRD3 and NSD3 fusion partners. Although NUT adnexal carcinomas are shown to have metastatic potential, they may behave less aggressively than extracutaneous NUT carcinomas. We report a case of a 59‐year‐old man who underwent a biopsy of a 3‐cm plantar mass, which showed BRD4::NUTM1 fusion. The tumor was a poorly differentiated dermal neoplasm showing cytologic atypia, large vesicular nuclei with prominent nucleoli, conspicuous mitotic activity, and foci of necrosis. Immunohistochemically, the tumor showed positivity for keratins, EMA, SOX10, and NUT, with patchy smooth muscle actin. Molecular testing revealed BRD4::NUTM1 rearrangement. With no alternative primary identified by imaging, a diagnosis of primary cutaneous NUT carcinoma was favored. We hope to contribute to the limited body of knowledge on this entity, with emphasis on recognition as well as studying and defining its prognostic differences from extracutaneous NUT carcinomas. [ABSTRACT FROM AUTHOR]

The immune system is an emerging regulator of hemostasis and thrombosis. The concept of immunothrombosis redefines the relationship between coagulation and immunomodulation, and the Gas6/Tyro3-Axl-MerTK (TAM) signaling pathway builds the bridge across them. During coagulation, Gas6/TAM signaling pathway not only activates platelets, but also promotes thrombosis through endothelial cells and vascular smooth muscle cells involved in inflammatory responses. Thrombosis appears to be a common result of a Gas6/TAM signaling pathway-mediated immune dysregulation. TAM TK and its ligands have been found to be involved in coagulation through the PI3K/AKT or JAK/STAT pathway in various systemic diseases, providing new perspectives in the understanding of immunothrombosis. Gas6/TAM signaling pathway serves as a breakthrough target for novel therapeutic strategies to improve disease management. Many preclinical and clinical studies of TAM receptor inhibitors are in process, confirming the pivotal role of Gas6/TAM signaling pathway in immunothrombosis. Therapeutics targeting the TAM receptor show potential both in anticoagulation management and immunotherapy. Here, we review the immunological functions of the Gas6/TAM signaling pathway in coagulation and its multiple mechanisms in diseases identified to date, and discuss the new clinical strategies that may generated by these roles. • Gas6/TAM signaling pathway bridges hemostasis and immunoregulation. • TAM receptor is a pivotal driver of immunothrombosis in diseases. • TAM receptor inhibitors are effective anticoagulants in preclinical studies, yet the clinical application is challenging. • Therapeutic strategies targeting TAM reveal great perspectives in therapy for immunothrombosis. [ABSTRACT FROM AUTHOR]

Plaque erosion, a type of coronary atherothrombosis, involves superficial injury to smooth muscle cell (SMC)-rich plaques. Elevated levels of coagulation factor VIII (FVIII) correlate with an increased ischemic heart disease risk. FVIII may contribute to thrombus formation on eroded plaques. We aimed to elucidate the role of elevated FVIII in arterial thrombus formation within SMC-rich neointima in rabbits. We assessed the effect of recombinant human FVIII (rFVIII) on blood coagulation in vitro and platelet aggregation ex vivo. An SMC-rich neointima was induced through balloon injury to the unilateral femoral artery. Three weeks after the first balloon injury, superficial erosive injury and thrombus formation were initiated with a second balloon injury of the bilateral femoral arteries 45 min after the administration of rFVIII (100 IU/kg) or saline. The thrombus area and contents were histologically measured 15 min after the second balloon injury. rFVIII administration reduced the activated partial thromboplastin time and augmented botrocetin-induced, but not collagen- or adenosine 5′-diphosphate-induced, platelet aggregation. While rFVIII did not influence platelet-thrombus formation in normal intima, it increased thrombus formation on SMC-rich neointima post-superficial erosive injury. Enhanced immunopositivity for glycoprotein IIb/IIIa and fibrin was observed in rFVIII-administered SMC-rich neointima. Neutrophil count in the arterial thrombus on the SMC-rich neointima correlated positively with thrombus size in the control group, unlike the rFVIII group. Increased FVIII contributes to thrombus propagation within erosive SMC-rich neointima, highlighting FVIII's potential role in plaque erosion-related atherothrombosis. • Recombinant VIII (rFVIII) does not affect thrombus formation on normal intima. • rFVIII enhances platelet-fibrin thrombus on smooth muscle cell-rich neointima. • Enhanced thrombosis under elevated FVIII is neutrophil-independent. [ABSTRACT FROM AUTHOR]

Adenomyosis (ADS) is a common benign gynecological disease. Abnormal proliferation at the endometrial-myometrial interface (EMI) plays a crucial role in the occurrence and progression of ADS. miR-141-3p is associated with cell proliferation and apoptosis. However, the specific mechanism of miR-141-3p in the etiology of ADS is still unknown. In this study, we explored the effects of miR-141-3p on the proliferation and apoptosis of ADS EMI smooth muscle cells (SMCs). We collected EMI tissues for the primary culture of SMCs from 25 patients diagnosed with ADS and 20 without ADS. Real-time quantitative polymerase chain reaction and western blot were used to measure the mRNA and protein expression levels of miR-141-3p, JAK2, STAT3, phospho-JAK2, and phospho-STAT3 in ADS EMI SMCs. The cell counting kit 8 assay and flow cytometry analysis were used to evaluate the proliferation and apoptosis of EMI SMCs. The miR-141-3p mimic/inhibitor was used to increase or decrease the expression level of miR-141-3p. We added WP1066 to block the phosphorylation of JAK2/STAT3 pathway components. The miR-141-3p levels were decreased, while JAK2 and STAT3 levels were increased in ADS EMI SMCs. miR-141-3p overexpression significantly inhibited the proliferation and enhanced the apoptosis of EMI SMCs, whereas a decrease in miR-141-3p expression level was connected to the opposite results. Meanwhile, inactivated JAK2/STAT3 pathway decreased proliferation and enhanced apoptosis of EMI SMCs after WP1066 treatment. Furthermore, rescue experiments confirmed that the JAK2/STAT3 pathway was the downstream pathway of miR-141-3p and reduced the effect of miR-141-3p on the proliferation and apoptosis of EMI SMCs. These results demonstrate that miR-141-3p regulates the proliferation and apoptosis of ADS EMI SMCs by modulating the JAK2/STAT3 pathway. [ABSTRACT FROM AUTHOR]

Given the insidious and high-fatality nature of cardiovascular diseases (CVDs), the emergence of fluoride as a newly identified risk factor demands serious consideration alongside traditional risk factors. While vascular smooth muscle cells (VSMCs) play a pivotal role in the progression of CVDs, the toxicological impact of fluoride on VSMCs remains largely uncharted. In this study, we constructed fluorosis model in SD rats and A7R5 aortic smooth muscle cell lines to confirm fluoride impaired VSMCs. Fluoride aggravated the pathological damage of rat aorta in vivo. Then A7R5 were exposed to fluoride with concentration ranging from 0 to 1200 μmol/L over a 24-h period, revealing a dose-dependent inhibition of cell proliferation and migration. The further metabolomic analysis showed alterations in metabolite profiles induced by fluoride exposure, notably decreasing organic acids and lipid molecules level. Additionally, gene network analysis underscored the frequency of fluoride's interference with amino acids metabolism, potentially impacting the tricarboxylic acid (TCA) cycle. Our results also highlighted the ATP-binding cassette (ABC) transporters pathway as a central element in VSMC impairment. Moreover, we observed a dose-dependent increase in osteopontin (OPN) and α-smooth muscle actin (α-SMA) mRNA level and a dose-dependent decrease in ABC subfamily C member 1 (ABCC1) and bestrophin 1 (BEST1) mRNA level. These findings advance our understanding of fluoride as a CVD risk factor and its influence on VSMCs and metabolic pathways, warranting further investigation into this emerging risk factor. [ABSTRACT FROM AUTHOR]

Background: MiRNA let7d‐5p has been recently reported to be abnormally expressed in diabetes‐associated atherosclerosis (AS). However, it still remains unknown how let7d‐5p contributes to the process of atherosclerosis. Methods: Twenty fresh tissues and a total of 28 wax block specimens from carotid endarterectomy procedures were obtained from the Luoyang Central Hospital affiliated to Zhengzhou University. The expression of let7d‐5p was assessed using quantitative RT‐PCR (qRT‐PCR). A series of in vitro experiments was used to determine the roles of let7d‐5p knockdown and overexpression in vascular smooth muscle cells (VSMCs). Results: We discovered that the carotid plaques from diabetic patients had lower expression levels of miR let7d‐5p. In VSMCs, the expression of miRNA let7d‐5p was significantly lower in high glucose conditions compared with low glucose situations. The proliferation and migration of VSMCs were also inhibited by the overexpression of let7d‐5p, whereas the opposite was true when let7d‐5p was inhibited, according to gain and loss of function studies. Mechanically, let7d‐5p might activate the GSK3β/β‐catenin signaling pathway via binding to the high mobility group AT‐Hook 2 (HMGA2) mRNA in VSMCs. Additionally, GLP‐1RA liraglutide may prevent the migration and proliferation of VSMCs by raising let7d‐5p levels. Conclusions: High glucose stimulated the proliferation and migration of VSMCs by regulating the let7d‐5p/HMGA2/GSK3β/β‐catenin pathway, and liraglutide may slow atherosclerosis by increasing the levels of miR let7d‐5p. [ABSTRACT FROM AUTHOR]

Objectives: Intimal hyperplasia is a serious clinical problem associated with the failure of therapeutic methods in multiple atherosclerosis-related coronary heart diseases, which are initiated and aggravated by the polarization of infiltrating macrophages. The present study aimed to determine the effect and underlying mechanism by which tumor necrosis factor receptor-associated factor 5 (TRAF5) regulates macrophage polarization during intimal hyperplasia. Methods: TRAF5 expression was detected in mouse carotid arteries subjected to wire injury. Bone marrow-derived macrophages, mouse peritoneal macrophages and human myeloid leukemia mononuclear cells were also used to test the expression of TRAF5 in vitro. Bone marrow-derived macrophages upon to LPS or IL-4 stimulation were performed to examine the effect of TRAF5 on macrophage polarization. TRAF5-knockout mice were used to evaluate the effect of TRAF5 on intimal hyperplasia. Results: TRAF5 expression gradually decreased during neointima formation in carotid arteries in a time-dependent manner. In addition, the results showed that TRAF5 expression was reduced in classically polarized macrophages (M1) subjected to LPS stimulation but was increased in alternatively polarized macrophages (M2) in response to IL-4 administration, and these changes were demonstrated in three different types of macrophages. An in vitro loss-of-function study with TRAF5 knockdown plasmids or TRAF5-knockout mice revealed high expression of markers associated with M1 macrophages and reduced expression of genes related to M2 macrophages. Subsequently, we incubated vascular smooth muscle cells with conditioned medium of polarized macrophages in which TRAF5 expression had been downregulated or ablated, which promoted the proliferation, migration and dedifferentiation of VSMCs. Mechanistically, TRAF5 knockdown inhibited the activation of anti-inflammatory M2 macrophages by directly inhibiting PPARγ expression. More importantly, TRAF5-deficient mice showed significantly aggressive intimal hyperplasia. Conclusions: Collectively, this evidence reveals an important role of TRAF5 in the development of intimal hyperplasia through the regulation of macrophage polarization, which provides a promising target for arterial restenosis-related disease management. [ABSTRACT FROM AUTHOR]

Introduction: Cross‐talk among biological pathways is essential for normal biological function and plays a significant role in cancer progression. Through integrated network analysis, this study explores the significance of pathway cross‐talk in colorectal cancer (CRC) development at both the pathway and gene levels. Methods: In this study, we integrated the gene expression data with domain knowledge to construct state‐dependent pathway cross‐talk networks. The significance of the genes involved in pathway cross‐talk was assessed by analyzing their association with cancer hallmarks, disease‐gene relation, genetic alterations, and survival analysis. We also analyzed the gene regulatory network to identify the dysregulated genes and their role in CRC progression. Results: Cross‐talk was observed between immune‐related pathways and pathways associated with cell communication and signaling. The PTPRC gene was identified as a mediator, facilitating interactions within the immune system and other signaling pathways. The rewired interactions of ITGA7 were identified as influential in the epithelial‐mesenchymal transition in CRC. This study also highlighted the crucial link between cell communication and vascular smooth muscle contraction pathway in CRC progression. The survival analysis of identified gene clusters showed their significant prognostic value in distinguishing high‐risk from low‐risk CRC groups, and L1000CDS2 revealed seven potential drug molecules in CRC. Nine dysregulated genes (CTNNB1, EP300, JUN, MYC, NFKB1, RELA, SP1, STAT1, and TP53) emerge as transcription factors acting as common regulators across various pathways. Conclusions: This study highlights the crucial role of pathway cross‐talk in CRC progression and identified the potential prognostic biomarkers and potential drug molecules. [ABSTRACT FROM AUTHOR]

Succinate dehydrogenase (SDH) is a key mitochondrial enzyme involved in the tricarboxylic acid cycle, where it facilitates the oxidation of succinate to fumarate, and is coupled to the reduction of ubiquinone in the electron transport chain as Complex II. Previously, we developed a confocal‐based quantitative histochemical technique to determine the maximum velocity of the SDH reaction (SDHmax) in single cells and observed that SDHmax corresponds with mitochondrial volume density. In addition, mitochondrial volume and motility varied within different compartments of human airway smooth muscle (hASM) cells. Therefore, we hypothesize that the SDH activity varies relative to the intracellular mitochondrial volume within hASM cells. Using 3D confocal imaging of labeled mitochondria and a concentric shell method for analysis, we quantified mitochondrial volume density, mitochondrial complexity index, and SDHmax relative to the distance from the nuclear membrane. The mitochondria within individual hASM cells were more filamentous in the immediate perinuclear region and were more fragmented in the distal parts of the cell. Within each shell, SDHmax also corresponded to mitochondrial volume density, where both peaked in the perinuclear region and decreased in more distal parts of the cell. Additionally, when normalized to mitochondrial volume, SDHmax was lower in the perinuclear region when compared to the distal parts of the cell. In summary, our results demonstrate that SDHmax measures differences in SDH activity within different cellular compartments. Importantly, our data indicate that mitochondria within individual cells are morphologically heterogeneous, and their distribution varies substantially within different cellular compartments, with distinct functional properties. [ABSTRACT FROM AUTHOR]

Aortic aneurysms (AA) and aorta dissection (AD) are life-threatening conditions with a rising incidence and high mortality rate. Recent research has linked non-coding RNAs to the regulation of AA and AD progression. In this study, we performed circRNA sequencing, microRNA (miRNA) sequencing, and messenger RNA (mRNA) sequencing on plasma samples from AA and AD patients to identify the key circRNA-miRNA-mRNA axis involved in the transition from AA to AD. Our results showed elevated levels of circ_0000006 and circ_0000160, along with decreased levels of hsa-let-7e-5p in AD samples compared to AA samples. Predictive analysis suggested that circ_0000006 and circ_0000160 potentially target hsa-let-7e-5p, which in turn may bind to the mRNA of Ubiquilin 4 (UBQLN4). In an AD cell model using vascular smooth muscle cells (VSMCs), silencing circ_0000006 and circ_0000160 attenuated the effects of platelet-derived growth factor (PDGF)-induced phenotypic changes, proliferation, and migration. This effect was partially reversed by inhibiting hsa-let-7e-5p. Furthermore, we found that overexpression of UBQLN4 counteracted the effects of hsa-let-7e-5p, suggesting UBQLN4 as a downstream mediator of hsa-let-7e-5p. In an animal model of AD, knockdown of circ_0000006 and circ_0000160 also showed protective effects against aortic septation. Overall, our findings indicate that the upregulation of circ_0000006 and circ_0000160 contributes to the progression from AA to AD by influencing abnormal phenotypic changes, migration, and proliferation of VSMCs. The Hsa-let-7e-5p/UBQLN4 axis may play a critical role in AD development. Targeting circ_0000006 and circ_0000160 could be a potential therapeutic strategy for preventing the progression of AD. [ABSTRACT FROM AUTHOR]

Background: Vascular calcification (VC) is an independent risk factor for cardiovascular diseases. Recently, ferroptosis has been recognised as a novel therapeutic target for cardiovascular diseases. Although an association between ferroptosis and vascular calcification has been reported, the role and mechanism of iron overload in vascular calcification are still poorly understood. Specifically, further in-depth research is required on whether metalloproteins SLC39a14 and SLC39a8 are involved in ferroptosis induced by iron overload. Methods: R language was employed for the differential analysis of the dataset, revealing the correlation between ferroptosis and calcification. The experimental approaches encompassed both in vitro and in vivo studies, incorporating the use of iron chelators and models of iron overload. Additionally, gain- and loss-of-function experiments were conducted to investigate iron's effects on vascular calcification comprehensively. Electron microscopy, immunofluorescence, western blotting, and real-time polymerase chain reaction were used to elucidate how Slc39a14 and Slc39a8 mediate iron overload and promote calcification. Results: Ferroptosis was observed in conjunction with vascular calcification (VC); the association was consistently confirmed by in vitro and in vivo studies. Our results showed a positive correlation between iron overload in VSMCs and calcification. Iron chelators are effective in reversing VC and iron overload exacerbates this process. The expression levels of the metal transport proteins Slc39a14 and Slc39a8 were significantly upregulated during calcification; the inhibition of their expression alleviated VC. Conversely, Slc39a14 overexpression exacerbates calcification and promotes intracellular iron accumulation in VSMCs. Conclusions: Our research demonstrates that iron overload occurs during VC, and that inhibition of Slc39a14 and Slc39a8 significantly relieves VC by intercepting iron overload-induced ferroptosis in VSMCs, providing new insights into the VC treatment. [ABSTRACT FROM AUTHOR]