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Hypoxia, a condition of oxygen tension lower than physiological level, plays a crucial role in shaping the tumor microenvironment and modulates distinct cell populations activity. The tumor suppressor PTEN regulates angiogenesis, a process involving endothelial cells (ECs). Pathological in tumors, it is crucial for growth. As PTEN modulates p53, a key regulator of the ECs growth/angiogenic activity, it appears to be a target enabling the repair of the pathologic angiogenesis. This study aims to compare ECs derived from breast cancer (HBCa.MEC) site with those derived from the healthy breast tissue (HBH.MEC). Hypoxia increased angiogenic activity in HBCa.MEC vs. HBH.MEC, as showed an increased. Ability to form vessels in vitro. Low pO2 reduced the total level of Mdm2 and PTEN protein expression leading to elevated levels of their phosphorylation-dependent activity in HBCa.MEC, what was not changed in healthy ECs. Additionally, when Mdm2-p53 interaction was inhibited, hypoxic HBCa.MEC angiogenic activity was reduced reaching the normoxic ECs response. In conclusion, the PTEN-mediated control of pathological angiogenesis occurs by modulation of Mdm2/p53 interaction in the context of breast tumor microenvironment. PTEN emerges as a potential therapeutic target for normalizing tumor vessels in breast cancer treatment strategies. [ABSTRACT FROM AUTHOR]

Background and Purpose Experimental Approach Key Results Conclusion and Implications Pathological retinal angiogenesis is a typical manifestation of vision‐threatening ocular diseases. Many patients exhibit poor response or resistance to anti‐vascular endothelial growth factor (VEGF) agents. Bruton's tyrosine kinase (BTK) controls the proliferation and function of immune cells. Therefore, we examined the anti‐inflammatory and anti‐angiogenic effects of BTK inhibition on retinal angiogenesis.Retinal neovascularisation and vascular leakage in oxygen‐induced retinopathy in C57/BL6J mice were assessed by whole‐mount retinal immunofluorescence. PLX5622 was used to deplete microglia and Rag1‐knockout mice were used to test the contribution of lymphocytes to the effects of BTK inhibition. The cytokines, activation markers, inflammatory and immune‐regulatory activities of retinal microglia/macrophages were detected using qRT‐PCR and immunofluorescence. NLRP3 was detected by western blotting, and the effects of BTK inhibition on the co‐culture of microglia and human retinal microvascular endothelial cells (HRMECs) were examined.BTK inhibition suppressed pathological angiogenesis and vascular leakage, and significantly reduced retinal inflammation, which involved microglia/macrophages but not lymphocytes. BTK inhibition increased anti‐inflammatory factors and reduced pro‐inflammatory cytokines that resulted from NLRP3 inflammasome activation. BTK inhibition suppressed the inflammatory activity of microglia/macrophages, and acted synergistically with anti‐VEGF without retinal toxicity. Moreover, the supernatant of microglia incubated with BTK‐inhibitor reduced the proliferation, tube formation and sprouting of HRMECs.BTK inhibition suppressed retinal neovascularisation and vascular leakage by modulating the inflammatory activity of microglia and macrophages. Our study suggests BTK inhibition as a novel and promising approach for alleviating pathological retinal angiogenesis. [ABSTRACT FROM AUTHOR]

Background: Dysfunction of retinal vascularization plays pathogenic roles in retinopathy of prematurity (ROP). Hypoxia-inducible factor 1 alpha (HIF1A) is activated by hypoxia and contributes to ROP progression. Herein, we clarified the mechanism underlying HIF1A activation in human retinal vascular endothelial cells (HRECs) under hypoxia. Methods: Protein expression was assayed by immunoblot analysis. Cell migration, microtubule formation, invasion, proliferation, and viability were detected by wound-healing, tube formation, transwell, EdU, and CCK-8 assays, respectively. Bioinformatics was used to predict the deubiquitinase-HIF1A interactions and RNA binding proteins (RBPs) bound to USP33. The impact of USP33 on HIF1A deubiquitination was validated by immunoprecipitation (IP) assay. RNA stability analysis was performed with actinomycin D (Act D) treatment. The ELAVL1/USP33 interaction was assessed by RNA immunoprecipitation experiment. Results: In hypoxia-exposed HRECs, HIF1A and USP33 protein levels were upregulated. Deficiency of HIF1A or USP33 suppressed cell migration, proliferation and microtubule formation of hypoxia-exposed HRECs. Mechanistically, USP33 deficiency led to an elevation in HIF1A ubiquitination and degradation. USP33 deficiency reduced HIF1A protein levels to suppress the proliferation and microtubule formation of hypoxia-induced HRECs. Moreover, the RBP ELAVL1 stabilized USP33 mRNA to increase USP33 protein levels. ELAVL1 decrease repressed the proliferation and microtubule formation of hypoxia-induced HRECs by reducing USP33. Conclusion: Our study identifies a novel ELAVL1/USP33/HIF1A regulatory cascade with the ability to affect hypoxia-induced pathological proliferation, angiogenesis, and migration in HRECs. [ABSTRACT FROM AUTHOR]

Abstract The microglia-mediated neuroinflammation have been shown to play a crucial role in the ocular pathological angiogenesis process, but specific immunotherapies for neovascular ocular diseases are still lacking. This study proposed that targeting GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) might be a novel immunotherapy for these angiogenesis diseases. We found a significant upregulation of CGAS and STING genes in the RNA-seq data derived from retinal tissues of the patients with proliferative diabetic retinopathy. In experimental models of ocular angiogenesis including laser-induced choroidal neovascularization (CNV) and oxygen-induced retinopathy (OIR), the cGAS-STING pathway was activated as angiogenesis progressed. Either genetic deletion or pharmacological inhibition of STING resulted in a remarkable suppression of neovascularization in both models. Furthermore, cGAS-STING signaling was specifically activated in myeloid cells, triggering the subsequent RIP1-RIP3-MLKL pathway activation and leading to necroptosis-mediated inflammation. Notably, targeted inhibition of the cGAS-STING pathway with C-176 or SN-011 could significantly suppress pathological angiogenesis in CNV and OIR. Additionally, the combination of C-176 or SN-011 with anti-VEGF therapy led to least angiogenesis, markedly enhancing the anti-angiogenic effectiveness. Together, our findings provide compelling evidence for the importance of the cGAS-STING-necroptosis axis in pathological angiogenesis, highlighting its potential as a promising immunotherapeutic target for treating neovascular ocular diseases.

The microglia-mediated neuroinflammation have been shown to play a crucial role in the ocular pathological angiogenesis process, but specific immunotherapies for neovascular ocular diseases are still lacking. This study proposed that targeting GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) might be a novel immunotherapy for these angiogenesis diseases. We found a significant upregulation of CGAS and STING genes in the RNA-seq data derived from retinal tissues of the patients with proliferative diabetic retinopathy. In experimental models of ocular angiogenesis including laser-induced choroidal neovascularization (CNV) and oxygen-induced retinopathy (OIR), the cGAS-STING pathway was activated as angiogenesis progressed. Either genetic deletion or pharmacological inhibition of STING resulted in a remarkable suppression of neovascularization in both models. Furthermore, cGAS-STING signaling was specifically activated in myeloid cells, triggering the subsequent RIP1-RIP3-MLKL pathway activation and leading to necroptosis-mediated inflammation. Notably, targeted inhibition of the cGAS-STING pathway with C-176 or SN-011 could significantly suppress pathological angiogenesis in CNV and OIR. Additionally, the combination of C-176 or SN-011 with anti-VEGF therapy led to least angiogenesis, markedly enhancing the anti-angiogenic effectiveness. Together, our findings provide compelling evidence for the importance of the cGAS-STING-necroptosis axis in pathological angiogenesis, highlighting its potential as a promising immunotherapeutic target for treating neovascular ocular diseases. [ABSTRACT FROM AUTHOR]

Objective To investigate the effect of silencing alpha tubulin acetyltransferase 1 (α-TAT1) on migration behavior of endothelial cells induced by hepatopulmonary syndrome (HPS). Methods Online database Tabula Muris was used to analyze the expression of α-TAT1 in various cell subsets in the lungs. Twenty-four male SD rats were randomly divided into control group (Sham group, n=6) and common bile duct ligation group (HPS group, n=18). The rats in HPS group were euthanasized at 2 and 4 weeks after modelling, and then the expression of α-TAT1 in pulmonary vascular endothelial cells was detected by immunofluorescence colocalization. The sera from the Sham and HPS rats were used to stimulate human umbilical vein endothelial cells (HUVECs) for 12 and 24 h, respectively. Then the obtained HUVECs were divided into 4 groups: Sham serum + siRNA NC group, Sham serum + siRNA α-TAT1 group, HPS serum+ siRNA NC group, HPS serum + siRNA α-TAT1 group. The expression levels of α-TAT1 and Ace-α-tubulin in HUVECs were detected by Western blotting. Immunofluorescence assay was applied to observe the levels of polymerized microtubules of α-Tubulin in HUVECs after nocodazole (10 μmol/L) pretreatment to evaluate the stability of microtubule structure. Cell scratch assay combined with cell immunofluorescence assay was employed to observe the nuclear localization of Golgi apparatus and cell migration ability of HUVECs. The angiogenesis ability of HUVECs was tested by in vitro angiogenesis test. Results In vivo and in vitro experiments showed that the expression of α-TAT1 in endothelial cells was significantly increased after HPS inducement. The expression levels of α-TAT1 and Ace-α-tubulin were significantly down-regulated, and the stability of microtubules was weakened in the siRNA α-TAT1 interference group (P < 0.01). In addition, the distribution of GM130 labeled Golgi apparatus in the protrusion of HUVECs was down-regulated in the siRNA α-TAT1 interference group, as well as the migration ability (P < 0.01). And the length of angiogenesis and network level were also significantly declined (P < 0.01). Conclusion Silencing α-TAT1 reduces the migration and angiogenesis of endothelial cells in HPS, which was associated with weakened stabilization of microtubule.

Ocular neovascularization can impair vision and threaten patients' quality of life. However, the underlying mechanism is far from transparent. In all mammals, macrophages are a population of cells playing pivotal roles in the innate immune system and the first line of defense against pathogens. Therefore, it has been speculated that the disfunction of macrophage homeostasis is involved in the development of ocular vascular diseases. Moreover, various studies have found that non-coding RNAs (ncRNAs) regulate macrophage homeostasis. This study reviewed past studies of the regulatory roles of ncRNAs in macrophage homeostasis in ocular vascular diseases. [ABSTRACT FROM AUTHOR]

Abstract Background Genetic analysis in human patients has linked mutations in PIK3CA, the catalytic subunit of PI‐3′Kinase, to sporadic incidences of vascular malformations. Methods We have developed a mouse model with inducible and endothelial‐specific expression of PIK3CAH1047R, resulting in the development of vascular malformations. Systemic induction of this mutation in adult mice results in rapid lethality, limiting our ability to track and study these lesions; therefore, we developed a topical and local induction protocol using the active metabolite of tamoxifen, 4OH‐T, on the ear skin of adults. Results This approach allows us to successfully model the human disease in a mature and established vascular bed and track the development of vascular malformations. To validate the utility of this model, we applied a topical rapamycin ointment, as rapamycin is therapeutically beneficial to patients in clinical trials. We found that the induced ear lesions showed significant attenuation after treatment, which was easily quantified. Conclusions These data collectively provide evidence of a new model to study vascular malformations in adult tissues, which should be particularly useful in environments lacking specialized small‐animal imaging facilities.

Hepatic fibrosis is the formation of scar tissue in the liver. This scar tissue replaces healthy liver tissue and can lead to liver dysfunction and failure if left untreated. It is usually caused by chronic liver disease, such as hepatitis B or C, alcohol abuse, or non-alcoholic fatty liver disease. Pathological angiogenesis plays a crucial role in the development of hepatic fibrosis by promoting the growth of new blood vessels in the liver. These new vessels increase blood flow to the damaged areas of the liver, which triggers the activation of hepatic stellate cells (HSCs). HSCs are responsible for producing excess collagen and other extracellular matrix proteins that contribute to the development of fibrosis. Pathological angiogenesis plays a crucial role in the development of hepatic fibrosis by promoting the growth of new blood vessels in the liver. These new vessels increase blood flow to the damaged areas of the liver, which triggers the activation of HSCs. HSCs are responsible for producing excess collagen and other extracellular matrix proteins that contribute to the development of fibrosis. Traditional Chinese medicine (TCM) has been found to target pathological angiogenesis, thereby providing a potential treatment option for hepatic fibrosis. Several studies have demonstrated that TCM exhibits anti-angiogenic effects by inhibiting the production of pro-angiogenic factors, such as vascular endothelial growth factor and angiopoietin-2, and by reducing the proliferation of endothelial cells. Reviewing and highlighting the unique TCM recognition of treating hepatic fibrosis by targeting pathological angiogenesis may shed light on future hepatic fibrosis research.

Ocular neovascularization can impair vision and threaten patients’ quality of life. However, the underlying mechanism is far from transparent. In all mammals, macrophages are a population of cells playing pivotal roles in the innate immune system and the first line of defense against pathogens. Therefore, it has been speculated that the disfunction of macrophage homeostasis is involved in the development of ocular vascular diseases. Moreover, various studies have found that non-coding RNAs (ncRNAs) regulate macrophage homeostasis. This study reviewed past studies of the regulatory roles of ncRNAs in macrophage homeostasis in ocular vascular diseases.

The nuclear factor of κ-light chain of enhancer-activated B cells (NF-κB) signaling pathway, which is conserved in invertebrates, plays a significant role in human diseases such as inflammation-related diseases and carcinogenesis. Angiogenesis refers to the growth of new capillary vessels derived from already existing capillaries and postcapillary venules. Maintaining normal angiogenesis and effective vascular function is a prerequisite for the stability of organ tissue function, and abnormal angiogenesis often leads to a variety of diseases. It has been suggested that NK- κ B signalling molecules under pathological conditions play an important role in vascular differentiation, proliferation, apoptosis and tumourigenesis by regulating the transcription of multiple target genes. Many NF- κ B inhibitors are being tested in clinical trials for cancer treatment and their effect on angiogenesis is summarised. In this review, we will summarise the role of NF- κ B signalling in various neovascular diseases, especially in tumours, and explore whether NF- κ B can be used as an attack target or activation medium to inhibit tumour angiogenesis. [ABSTRACT FROM AUTHOR]

Diabetic retinopathy (DR) is a chronic disease associated with diabetes mellitus and is a leading cause of visual impairment among the working population in the US. Clinically, DR has been diagnosed and treated as a vascular complication, but it adversely impacts both neural retina and retinal vasculature. Degeneration of retinal neurons and microvasculature manifests in the diabetic retina and early stages of DR. Retinal photoreceptors undergo apoptosis shortly after the onset of diabetes, which contributes to the retinal dysfunction and microvascular complications leading to vision impairment. Chronic inflammation is a hallmark of diabetes and a contributor to cell apoptosis, and retinal photoreceptors are a major source of intraocular inflammation that contributes to vascular abnormalities in diabetes. As the levels of microRNAs (miRs) are changed in the plasma and vitreous of diabetic patients, miRs have been suggested as biomarkers to determine the progression of diabetic ocular diseases, including DR. However, few miRs have been thoroughly investigated as contributors to the pathogenesis of DR. Among these miRs, miR-150 is downregulated in diabetic patients and is an endogenous suppressor of inflammation, apoptosis, and pathological angiogenesis. In this review, how miR-150 and its downstream targets contribute to diabetes-associated retinal degeneration and pathological angiogenesis in DR are discussed. Currently, there is no effective treatment to stop or reverse diabetes-caused neural and vascular degeneration in the retina. Understanding the molecular mechanism of the pathogenesis of DR may shed light for the future development of more effective treatments for DR and other diabetes-associated ocular diseases. [ABSTRACT FROM AUTHOR]

The growth of blood vessels from already existing vasculature is angiogenesis and it is one of the fundamental processes in fetal development, tissue damage or repair, and the reproductive cycle. In a healthy person, angiogenesis is regulated by the balance between pro- and anti-angiogenic factors. However, when the balance is disturbed, it results in various diseases or disorders. The angiogenesis pathway is a sequential cascade and differs based on the stimuli. Therefore, targeting one of the factors involved in the process can help us find a therapeutic strategy to treat irregular angiogenesis. In the past three decades of cancer research, angiogenesis has been at its peak, where an anti-angiogenic agent inhibiting vascular endothelial growth factor acts as a promising substance to treat cancer. In addition, cancer can be assessed based on the expression of angiogenic factors and its response to therapies. Angiogenesis is important for all tissues, which might be normal or pathologically changed and occur through ages. In clinical therapeutics, target therapy focusing on discovery of novel anti-angiogenic agents like bevacizumab, cetuximab, sunitinib, imatinib, lenvatinib, thalidomide, everolimus etc., to block or inhibit the angiogenesis pathway is well explored in recent times. In this review, we will discuss about the molecular signaling pathways involved in major angiogenic diseases in detail. [ABSTRACT FROM AUTHOR]

Synthesis and anti-angiogenic efficacy of tFNA@AF. Excessive angiogenesis is stimulated by the unbalance between pro-angiogenic and anti-angiogenic factors under pathological circumstances. The tFNA@AF could effectively block the interaction between vascular endothelial growth factor receptor 1 (VEGFR1) and its ligands, resulting in the inactivation of downstream PI3K/AKT/m-TOR signaling pathway. Regulating uncontrolled angiogenesis, the tFNA@AF shows exciting application potential in tumor progression and cornea injury. [Display omitted] • Low solubility, instability limit the application of anti-Flt 1 peptide. • tFNA provides an effective and safe strategy for AF delivery. • AF-functionalized DNA tetrahedron showed enhanced inhibitory effect on angiogenesis. Angiogenesis is an important and necessary process in tissue regeneration and recovery, but suppressing such process is also a critical therapeutic consideration in some diseases including tumor and corneal neovascularization. Currently, pathological angiogenesis is mainly inhibited through the blockade of the interaction between vascular endothelial growth factor receptor (VEGFR) and its ligands. Compared to traditional anti-angiogenic agents such as monoclonal antibody and tyrosine kinase inhibitor, polypeptide has gained growing interests for high unit activity, few adverse reactions, and low costs. Among them, anti-Flt1 (AF) peptide could inhibit VEGFR1-induced endothelial cell migration and tube formation, showing excellent anti-angiogenic activity. Addressing the issues of low water solubility, instability, and poor bioavailability would significantly hinder the applications of AF. Herein, we prepared an AF functionalized tetrahedral framework nucleic acid (tFNA@AF) to overcome the abovementioned limitations of AF. The tFNA@AF presented enhanced structural stability and cellular uptake of AF, and exhibited superior bioavailability and satisfying anti-angiogenic effectiveness in vitro. Furthermore, tFNA@AF also demonstrated high-efficiency pathological angiogenesis inhibition on tumor-bearing mice of triple-negative breast cancer and corneal neovascularization of cornea cauterized rats, two typical models of tumor and traumatic cornea where angiogenesis is not anticipant. Our tFNA@AF as a novel polypeptide-nucleic acid conjugated nanomaterials showed superior bioavailability and high anti-angiogenic effectiveness, suggesting that with incremental improvements the nanomedicine may offer potentially useful treatment aid for anti-angiogenic therapy to prevent tumor growth and corneal neovascularization. [ABSTRACT FROM AUTHOR]

Ischemic retinopathies (IR) are vision-threatening diseases that affect a substantial amount of people across all age groups worldwide. The current treatment options of photocoagulation and anti-VEGF therapy have side effects and are occasionally unable to prevent disease progression. It is therefore worthwhile to consider other molecular targets for the development of novel treatment strategies that could be safer and more efficient. During the manifestation of IR, the retina, normally an immune privileged tissue, encounters enhanced levels of cellular stress and inflammation that attract mononuclear phagocytes (MPs) from the blood stream and activate resident MPs (microglia). Activated MPs have a multitude of effects within the retinal tissue and have the potential to both counter and exacerbate the harmful tissue microenvironment. The present review discusses the current knowledge about the role of inflammation and activated retinal MPs in the major IRs: retinopathy of prematurity and diabetic retinopathy. We focus particularly on MPs and their secreted factors and cell–cell-based interactions between MPs and endothelial cells. We conclude that activated MPs play a major role in the manifestation and progression of IRs and could therefore become a promising new target for novel pharmacological intervention strategies in these diseases. [ABSTRACT FROM AUTHOR]

Regardless of the great progress in studying the heart failure (HF) pathophysiology, the question about involvement of immune cells activation, systemic inflammation, inflammatory cytokine dysregulation and endothelial dysfunction in maladaptive left ventricular (LV) remodeling in ischemic and nonischemic HF patients is still open to discussion. The aim was to study the characteristics of immunopathological reactions (immunoinflammatory and autoimmune), endothelial dysfunction and pathologic angiogenesis in maladaptive LV remodeling in ischemic and nonischemic HF patients. Materials and methods. A total of 20 healthy volunteers, 31 ischemic HF patients (group 1) and 43 nonischemic HF patients (group 2) were enrolled in the study. All the patients underwent coronarography, ventriculography, echocardigraphic examination. The main lymphocyte subset counts (flow cytometry), serum concentration of C-reactive protein (CRP), vascular endothelial growth factor A (VEGF), TNFα, endothelin-1 (enzyme-linked immunosorbent assay (ELISA)), autoantibodies to myocardium and vessels were detected. Results. Regardless of the HF etiology, all the examined patients demonstrated echocardiographic features of maladaptive LV remodeling and severe intracardiac hemodynamic disorders that was associated with immune system activation, namely increased total and subset lymphocyte counts, chronic systemic inflammation (CRP), autoimmune process with an increase in autoantibodies to myocardium and vessels, and endothelial dysfunction (increased endothelin-1 and VEGF). Under-expression of TNF-α combined with over-expression of VEGF seemed to indicate pathological angiogenesis in ischemic and nonischemic HF patients Conclusions. Significantly increased VEGF levels in heart failure patients can be considered as additional integral key marker of immune inflammation, endothelial dysfunction and pathological angiogenesis and may indicate maladaptive cardiac remodeling in severe heart failure.

Background: Bone marrow angiogenesis is increased in multiple myeloma (MM) patients, prompting the rationale for using antiangiogenic drugs in the treatment of these patients. Objective: To assess angiogenesis in patients with MM at diagnosis and following treatment with an antiangiogenic drug. Patients and Methods: Twenty-three patients with newly diagnosed MM were treated with thalidomide-based regimens. Bone marrow evaluation was made before and following treatment and included angiogenesis assessment, which was quantified through microvessel density (MVD) determination, by means of anti-CD34 immunohistochemical labeling, and classified either as high MVD or low MVD, according to the mean CD34 count: above or below the median of 12.6. Results: The pre-therapy median MVD was 12 (7.5–18.3) versus 8.7 (5.35–18.5) post-therapy, p = 0.2114. Conclusions: Our study found no reduction in MVD before and following treatment and, accordingly, we could establish no relationship between MVD and response to therapy in the sample we studied.

Conventional angiogenic factors, such as vascular endothelial growth factor (VEGF), regulate both pathological and physiological angiogenesis indiscriminately, and their inhibitors may elicit adverse side effects. Secretogranin III (Scg3) was recently reported to be a diabetes-restricted VEGF-independent angiogenic factor, but the disease selectivity of Scg3 in retinopathy of prematurity (ROP), a retinal disease in preterm infants with concurrent pathological and physiological angiogenesis, was not defined. Here, using oxygen-induced retinopathy (OIR) mice, a surrogate model of ROP, we quantified an exclusive binding of Scg3 to diseased versus healthy developing neovessels that contrasted sharply with the ubiquitous binding of VEGF. Functional immunohistochemistry visualized Scg3 binding exclusively to disease-related disorganized retinal neovessels and neovascular tufts, whereas VEGF bound to both disorganized and well-organized neovessels. Homozygous deletion of the Scg3 gene showed undetectable effects on physiological retinal neovascularization but markedly reduced the severity of OIR-induced pathological angiogenesis. Furthermore, anti-Scg3 humanized antibody Fab (hFab) inhibited pathological angiogenesis with similar efficacy to anti-VEGF aflibercept. Aflibercept dose-dependently blocked physiological angiogenesis in neonatal retinas, whereas anti-Scg3 hFab was without adverse effects at any dose and supported a therapeutic window at least 10X wider than that of aflibercept. Therefore, Scg3 stringently regulates pathological but not physiological angiogenesis, and anti-Scg3 hFab satisfies essential criteria for development as a safe and effective disease-targeted anti-angiogenic therapy for ROP. [ABSTRACT FROM AUTHOR]

Retinal angiogenesis is a critical process for normal retinal function. However, uncontrolled angiogenesis can lead to pathological neovascularization (NV), which is closely related to most irreversible blindness-causing retinal diseases. Understanding the molecular basis behind pathological NV is important for the treatment of related diseases. Twist-related protein 1 (TWIST1) is a well-known transcription factor and principal inducer of epithelialmesenchymal transition (EMT) in many human cancers. Our previous study showed that Twist1 expression is elevated in pathological retinal NV. To date, however, the role of TWIST1 in retinal pathological angiogenesis remains to be elucidated. To study the role of TWIST1 in pathological retinal NV and identify specific molecular targets for antagonizing pathological NV, we generated an inducible vascular endothelial cell (EC)-specific Twist1 transgenic mouse model (Tg-Twist1iEC+ ). Whole-mount retinas from Tg-Twist1iEC+ mice showed retarded vascular progression and increased vascular density in the front end of the growing retinal vasculature, as well as aneurysm-like pathological retinal NV. Furthermore, overexpression of Twist1 in the ECs promoted cell proliferation but disturbed cell polarity, thus leading to uncontrolled retinal angiogenesis. TWIST1 promoted pathological NV by activating the Wnt/β-catenin signaling pathway and inducing the expression of NV formation-related genes, thereby acting as a ‘valve’ in the regulation of pathological angiogenesis. This study identified the critical role of TWIST1 in retinal pathological NV, thus providing a potential therapeutic target for pathological NV. [ABSTRACT FROM AUTHOR]

The article is dedicated to contemporary views on the change of endothelial function in the patients with lymphoproliferative disorders prior to, and in the process of, chemotherapeutic treatment. Considering that possibilities of standard examination do not always help identifying subclinical endothelial dysfunction, it is necessary to use specific methods, in particular, to determine the levels of endothelin-1 and vascular endothelial growth factor to monitor endothelial function. The objective of this review is to identify problems and prospects for recognizing early subclinical changes of endothelial function in the patients with lymphoproliferative disorders before and after chemotherapy. Assessing presence and severity of endothelial dysfunction may be useful for determining subclinical stages of cardiovascular damage, stratifying the risk of the patients with confirmed cardiovascular disease, and reducing the likelihood of cardio- and endotheliotoxic effects in patients long after chemotherapy. That is why early detection and immediate therapy of cardiovascular toxicity is currently the most important task in the patients with lymphoproliferative disorders, receiving chemotherapy.

Background: To circumvent possible systemic side effects, anti-angiogenic drugs targeting vascular endothelial growth factor (VEGF) for ocular neovascular diseases in adults are approved only for intravitreal administration. However, intravitreal injection itself can elicit injection-related adverse effects, and premature eyes of infants with retinopathy of prematurity (ROP) may be particularly susceptible to intravitreal injection. Therefore, an unmet clinical need is to develop safe systemic anti-angiogenic therapies for ROP. We recently reported that secretogranin III (Scg3) is a disease-restricted angiogenic factor and that systemic anti-Scg3 mAb alleviates ROP in animal models with minimal side effects on developing eyes and organs. The aim of this study is to investigate the safety and efficacy of a humanized anti-Scg3 antibody via systemic administration. Methods: We analyzed the safety and efficacy of a humanized anti-Scg3 antibody Fab fragment (hFab) delivered by intraperitoneal injection in oxygen-induced retinopathy (OIR) mice, a surrogate model of ROP. Results: The results showed that systemic anti-Scg3 hFab effectively alleviated pathological retinal neovascularization in OIR mice with similar efficacy to the anti-VEGF drug aflibercept. Systemic aflibercept conferred significant adverse side effects in neonatal mice, including reduced body weight, abnormalities in retinal and renal development, and retarded physiological neovascularization, whereas systemic anti-Scg3 hFab elicited no such side effects. Conclusions: The findings suggest that systemic anti-Scg3 hFab is a safe and effective therapy for OIR and support further development for ROP treatment.

Background/Aims: Angiogenesis is a key feature during embryo development but is also part of the pathogenesis of cancer in adult life. Angiogenesis might be modulated by inflammation. Methods: We established an angiogenesis model in chick chorioallantoic membrane (CAM) induced by the exposure of lipopolysaccharide (LPS), and analyzed the effects of the antioxidant N-acetylcysteine (NAC) on angiogenesis in this model as well as on the expression of key genes known to involved in the regulation of angiogenesis. Results: Treatment with NAC was able to normalize LPS induced angiogenesis and restore the LPS-induced damage of vascular epithelium in chick CAM. Using quantitative PCR, we showed that NAC administration normalized the LPS induced expression of Keap1-Nrf2 signaling and oxidative stress key enzyme gene expressions (SOD, GPx and YAP1). Conclusion: We established a LPS-induced angiogenesis model in chick CAM. NAC administration could effectively inhibit LPS-induced angiogenesis and restore the integrity of endothelium on chick CAM. LPS exposure caused an increased expression of genes involved in oxidative stress in chick CAM. NAC administration could abolish this effect.

Engineering exosomes with nanomaterials usually leads to the damage of exosomal membrane and bioactive molecules. Here, pathological angiogenesis targeting exosomes with magnetic imaging, ferroptosis inducing, and immunotherapeutic properties is fabricated using a simple coincubation method with macrophages being the bioreactor. Extremely small iron oxide nanoparticle (ESIONPs) incorporated exosomes (ESIONPs@EXO) are acquired by sorting the secreted exosomes from M1-polarized macrophages induced by ESIONPs. ESIONPs@EXO suppress pathological angiogenesis in vitro and in vivo without toxicity. Furthermore, ESIONPs@EXO target pathological angiogenesis and exhibit an excellent T1-weighted contrast property for magnetic resonance imaging. Mechanistically, ESIONPs@EXO induce ferroptosis and exhibit immunotherapeutic ability toward pathological angiogenesis. These findings demonstrate that a pure biological method engineered ESIONPs@EXO using macrophages shows potential for targeted pathological angiogenesis therapy.

Aptamers are single-stranded DNA or RNA oligonucleotides that are currently used in clinical trials due to their selectivity and specificity to bind small molecules such as proteins, peptides, viral particles, vitamins, metal ions and even whole cells. Aptamers are highly specific to their targets, they are smaller than antibodies and fragment antibodies, they can be easily conjugated to multiple surfaces and ions and controllable post-production modifications can be performed. Aptamers have been therapeutically used for age-related macular degeneration, cancer, thrombosis and inflammatory diseases. The aim of this review is to highlight the therapeutic, diagnostic and prognostic possibilities associated with aptamers, focusing on eye pathological angiogenesis.

Angiogenesis, a process of new blood vessel formation from the pre-existing vascular bed, is a critical event in various physiological and pathological settings. Over the last few years, the role of endothelial cell (EC) metabolism in angiogenesis has received considerable attention. Accumulating studies suggest that ECs rely on aerobic glycolysis, rather than the oxidative phosphorylation pathway, to produce ATP during angiogenesis. To date, numerous critical regulators of glucose metabolism, fatty acid oxidation, and glutamine metabolism have been identified to modulate the EC angiogenic switch and pathological angiogenesis. The unique glycolytic feature of ECs is critical for cell proliferation, migration, and responses to environmental changes. In this review, we provide an overview of recent EC glucose metabolism studies, particularly glycolysis, in quiescent and angiogenic ECs. We also summarize and discuss potential therapeutic strategies that take advantage of EC metabolism. The elucidation of metabolic regulation and the precise underlying mechanisms could facilitate drug development targeting EC metabolism to treat angiogenesis-related diseases.

Hepatic fibrosis is the formation of scar tissue in the liver. This scar tissue replaces healthy liver tissue and can lead to liver dysfunction and failure if left untreated. It is usually caused by chronic liver disease, such as hepatitis B or C, alcohol abuse, or non-alcoholic fatty liver disease. Pathological angiogenesis plays a crucial role in the development of hepatic fibrosis by promoting the growth of new blood vessels in the liver. These new vessels increase blood flow to the damaged areas of the liver, which triggers the activation of hepatic stellate cells (HSCs). HSCs are responsible for producing excess collagen and other extracellular matrix proteins that contribute to the development of fibrosis. Pathological angiogenesis plays a crucial role in the development of hepatic fibrosis by promoting the growth of new blood vessels in the liver. These new vessels increase blood flow to the damaged areas of the liver, which triggers the activation of HSCs. HSCs are responsible for producing excess collagen and other extracellular matrix proteins that contribute to the development of fibrosis. Traditional Chinese medicine (TCM) has been found to target pathological angiogenesis, thereby providing a potential treatment option for hepatic fibrosis. Several studies have demonstrated that TCM exhibits anti-angiogenic effects by inhibiting the production of pro-angiogenic factors, such as vascular endothelial growth factor and angiopoietin-2, and by reducing the proliferation of endothelial cells. Reviewing and highlighting the unique TCM recognition of treating hepatic fibrosis by targeting pathological angiogenesis may shed light on future hepatic fibrosis research., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Li, Zhu and Ouyang.)

Background/Aims: Angiogenesis is a key feature during embryo development but is also part of the pathogenesis of cancer in adult life. Angiogenesis might be modulated by inflammation. Methods: We established an angiogenesis model in chick chorioallantoic membrane (CAM) induced by the exposure of lipopolysaccharide (LPS), and analyzed the effects of the antioxidant N-acetylcysteine (NAC) on angiogenesis in this model as well as on the expression of key genes known to involved in the regulation of angiogenesis. Results: Treatment with NAC was able to normalize LPS induced angiogenesis and restore the LPS-induced damage of vascular epithelium in chick CAM. Using quantitative PCR, we showed that NAC administration normalized the LPS induced expression of Keap1-Nrf2 signaling and oxidative stress key enzyme gene expressions (SOD, GPx and YAP1). Conclusion: We established a LPS-induced angiogenesis model in chick CAM. NAC administration could effectively inhibit LPS-induced angiogenesis and restore the integrity of endothelium on chick CAM. LPS exposure caused an increased expression of genes involved in oxidative stress in chick CAM. NAC administration could abolish this effect. [ABSTRACT FROM AUTHOR]

Proliferative diabetic retinopathy (PDR) adversely affects visual function. Extracellular matrix proteins (ECM) contribute significantly to the development of PDR. A Disintegrin and Metalloproteinase with Thrombospondin motifs 5 (ADAMTS5) is a member of ECM proteins. ADAMTS5 participates in angiogenesis and inflammation in diverse diseases. However, the role of ADAMTS5 in PDR remains elusive. Multiplex beam array technology was used to analyze vitreous humor of PDR patients and normal people. ELISA and Western blot were used to detect the expression of ADAMTS5, PEDF and autophagy related factors. Immunofluorescence assay was used to mark the expression and localization of ADAMTS5 and PEDF. The neovascularization was detected by tube formation test. Our results revealed that ADAMTS5 expression was increased in the vitreous humor of PDR patients and oxygen-induced retinopathy (OIR) mice retinas. Inhibiting ADAMTS5 alleviated pathological angiogenesis and upregulated PEDF expression in the OIR mice. In addition, ADAMTS5 inhibited PEDF secretion in ARPE-19 cells in vitro studies, thereby inhibiting the migration of HMEC-1. Mechanically, ADAMTS5 promoted the autophagic degradation of PEDF. Collectively, inhibition of ADAMTS5 during OIR suppresses pathological angiogenesis. Our study provides a new approach for resolving pathological angiogenesis in PDR. • We confirmed the role of ADAMTS5 in retinal neovascularization. • ADAMTS5 exerts its anti-angiogenesis effect and then inhibits proliferative diabetic retinopathy (PDR). • We provide a new target for proliferative diabetic retinopathy (PDR) treatment. [ABSTRACT FROM AUTHOR]

Pathological angiogenesis plays a major role in many disease processes, including cancer and diabetic retinopathy. Antiangiogenic therapy is a potential management for pathologic angiogenesis. The novel synthetic compound 221S-1a, derived from captopril, tanshinol and borneol, may have antiangiogenic properties. On the basis of MS, NMR and HPLC analysis, the structure of 221S-1a was identified. The cellular uptake and metabolism of this compound was also observed. Next, the antiangiogenic properties of 221S-1a were evaluated in tumor-xenograft and OIR models in vivo. The inhibitory properties of 221S-1a on endothelial cell proliferation, migration, tube formation and sprouting were detected in vitro. Furthermore, 221S-1a induced G1/S phase arrest was detected by PI staining flow cytometry analysis and Cyclin D, Cyclin E expression. 221S-1a inhibited ERK1/2 activation and nuclear translocation, in addition to downregulation of c-Myc, a transcription factor that regulates cell cycle progression. Molecular docking indicated the interaction of 221S-1a with the ATP-binding site of ERK2, leading to the inhibition of ERK2 phosphorylation and a concomitant inhibition of ERK1 phosphorylation. In conclusion, 221S-1a inhibited the G1/S phase transition by blocking the ERK1/2/c-Myc pathway to reduce tumor and OIR retinal angiogenesis. These novel findings suggest that 221S-1a is a potential pharmacologic candidate for treating pathological angiogenesis. [ABSTRACT FROM AUTHOR]

A number of anti-angiogenesis drugs have been FDA-approved and are being used in cancer treatment, and a number of other agents are in different stages of clinical development or in preclinical evaluation. However, pharmacologic anti-angiogenesis strategies that arrest tumor progression might not be enough to eradicate tumors. Decreased anti-angiogenesis activity in single mechanism-based anti-angiogenic strategies is due to the redundancy, multiplicity, and development of compensatory mechanism by which blood vessels are remodeled. Improving anti-angiogenesis drug efficacy will require identification of broad-spectrum anti-angiogenesis targets. These strategies may have novel features, such as increased porosity, and are the result of complex interactions among endothelial cells, extracellular matrix proteins, growth factors, pericyte, and smooth muscle cells. Thus, combinations of anti-angiogenic drugs and other anticancer strategies such as chemotherapy appear essential for optimal outcome in cancer patients. This review will focus on the role of anti-angiogenesis strategies in cancer treatment. [ABSTRACT FROM AUTHOR]

The signalling system known as mammalian target of rapamycin (mTOR) is believed to be required for several biological activities involving cell proliferation. The serine-threonine kinase identified as mTOR recognises PI3K-AKT stress signals. It is well established in the scientific literature that the deregulation of the mTOR pathway plays a crucial role in cancer growth and advancement. This review focuses on the normal functions of mTOR as well as its abnormal roles in cancer development. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Genetic analysis in human patients has linked mutations in PIK3CA, the catalytic subunit of PI-3'Kinase, to sporadic incidences of vascular malformations., Methods: We have developed a mouse model with inducible and endothelial-specific expression of PIK3CA H1047R , resulting in the development of vascular malformations. Systemic induction of this mutation in adult mice results in rapid lethality, limiting our ability to track and study these lesions; therefore, we developed a topical and local induction protocol using the active metabolite of tamoxifen, 4OH-T, on the ear skin of adults., Results: This approach allows us to successfully model the human disease in a mature and established vascular bed and track the development of vascular malformations. To validate the utility of this model, we applied a topical rapamycin ointment, as rapamycin is therapeutically beneficial to patients in clinical trials. We found that the induced ear lesions showed significant attenuation after treatment, which was easily quantified., Conclusions: These data collectively provide evidence of a new model to study vascular malformations in adult tissues, which should be particularly useful in environments lacking specialized small-animal imaging facilities., (© 2023 The Authors. Animal Models and Experimental Medicine published by John Wiley & Sons Australia, Ltd on behalf of The Chinese Association for Laboratory Animal Sciences.)

Accumulative evidences have underpinned the nature candidates from Chinese medicine (CM), particularly CM served as blood activating and stasis resolving (BASR, Huoxue Huayu in Chinese) by targeting tumor-associated angiogenesis. However, recent experiment research on the therapeutic angiogenesis by BASR-CM attracts wide attention and discussion. This opinion review focused on the underlying link between two indications and anticipated that (1) BASR-CM might emphasize on a balanced multi-cytokines network interaction; (2) BASR-CM might address on the nature of diseases prior to differently affecting physiological and pathological angiogenesis; (3) BASR-CM might mainly act on perivascular cells, either promotes arteriogenesis by increasing arteriogenic factors in ischemic diseases, or simultaneously keep a quiescent vasculature to impede angiogenesis in tumor context. [ABSTRACT FROM AUTHOR]