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The case of a 75‐year‐old man with a glioblastoma of the right frontal lobe showing features of adenoid glioblastoma is reported. The tumor consisted of two components: the adenoid component, in which large, cohesive, polygonal cells with vesicular nuclei and abundant basophilic cytoplasm showed nest‐like, trabecular, or tubular growth on the myxoid matrix and formed a multinodular configuration; and the subsidiary component, in which short spindle cells showed compact fascicular growth. The features of ordinary glioblastoma were also found in a small area. Tumor cells were immunoreactive for S‐100 protein, glial fibrillary acidic protein, and Olig2, and some tumor cells in the adenoid component showed immunoreactivity for cytokeratins and E‐cadherin. A marked regional decrease in microvascular density, approaching almost complete absence of microvessels, was demonstrated in the adenoid component. In contrast, microvascular density was well preserved in the spindle cell component and the area of ordinary glioblastoma. Tumor cells in the adenoid component showed cytoplasmic expression of chondromodulin‐I, one of the cytokines that strongly inhibit angiogenesis, whereas the expression of this protein was very weak or only faint in the spindle cell component and the area of ordinary glioblastoma. A marked regional decrease in microvascular density was associated with myxoid change of the stroma and considered to be caused by the secretion of chondromodulin‐I by tumor cells. Stromal hypovascularity with myxoid change might play an important role in the morphogenesis of adenoid features. [ABSTRACT FROM AUTHOR]

Duchenne muscular dystrophy (DMD) is a degenerative neuromuscular disease caused by a lack of functional dystrophin. Ang 1 paracrine signalling maintains the endothelial barrier of blood vessels, preventing plasma leakage. Chronic inflammation, a consequence of DMD, causes endothelial barrier dysfunction in skeletal muscle. We aim to elucidate changes in the DMD mouse's gastrocnemius microvascular niche following local administration of Ang 1. Gastrocnemii were collected from eight-week-old mdx/utrn+/− and healthy mice. Additional DMD cohort received an intramuscular injection of Ang 1 to gastrocnemius and contralateral control. Gastrocnemii were collected for analysis after two weeks. Using immunohistochemistry and real-time quantitative reverse transcription, we demonstrated an abundance of endothelial cells in DMD mouse's gastrocnemius, but morphology and gene expression were altered. Myofiber perimeters were shorter in DMD mice. Following Ang 1 treatment, fewer endothelial cells were present, and microvessels were more circular. Vegfr1, Vegfr2, and Vegfa expression in Ang 1-treated gastronemii increased, while myofiber size distribution was consistent with vehicle-only gastrocnemii. These results suggest robust angiogenesis in DMD mice, but essential genes were underexpressed—furthermore, exogenous Ang 1 attenuated angiogenesis. Consequentially, gene expression increased. The impact must be investigated further, as Ang 1 therapy may be pivotal in restoring the skeletal muscle microvascular niche. [ABSTRACT FROM AUTHOR]

Microvascular changes are considered key factors in the process of intervertebral disk degeneration (IDD). Microvascular invasion and growth into the nucleus pulposus (NP) and cartilaginous endplates are unfavorable factors that trigger IDD. In contrast, the rich distribution of microvessels in the bony endplates and outer layers of the annulus fibrosus is an important safeguard for the nutrient supply and metabolism of the intervertebral disk (IVD). In particular, the adequate supply of microvessels in the bony endplates is the main source of the nutritional supply for the entire IVD. Microvessels can affect the progression of IDD through a variety of pathways. Many studies have explored the effects of microvessel alterations in the NP, annulus fibrosus, cartilaginous endplates, and bony endplates on the local microenvironment through inflammation, apoptosis, and senescence. Studies also elucidated the important roles of microvessel alterations in the process of IDD, as well as conducted in‐depth explorations of cytokines and biologics that can inhibit or promote the ingrowth of microvessels. Therefore, the present manuscript reviews the published literature on the effects of microvascular changes on IVD to summarize the roles of microvessels in IVD and elaborate on the mechanisms of action that promote or inhibit de novo microvessel formation in IVD. [ABSTRACT FROM AUTHOR]

Cardiovascular diseases, particularly ischemic heart disease, area leading cause of morbidity and mortality worldwide. Myocardial infarction (MI) results in extensive cardiomyocyte loss, inflammation, extracellular matrix (ECM) degradation, fibrosis, and ultimately, adverse ventricular remodeling associated with impaired heart function. While heart transplantation is the only definitive treatment for end-stage heart failure, donor organ scarcity necessitates the development of alternative therapies. In such cases, methods to promote endogenous tissue regeneration by stimulating growth factor secretion and vascular formation alone are insufficient. Techniques for the creation and transplantation of viable tissues are therefore highly sought after. Approaches to cardiac regeneration range from stem cell injections to epicardial patches and interposition grafts. While numerous preclinical trials have demonstrated the positive effects of tissue transplantation on vasculogenesis and functional recovery, long-term graft survival in large animal models is rare. Adequate vascularization is essential for the survival of transplanted tissues, yet pre-formed microvasculature often fails to achieve sufficient engraftment. Recent studies report success in enhancing cell survival rates in vitro via tissue perfusion. However, the transition of these techniques to in vivo models remains challenging, especially in large animals. This review aims to highlight the evolution of cardiac patch and stem cell therapies for the treatment of cardiovascular disease, identify discrepancies between in vitro and in vivo studies, and discuss critical factors for establishing effective myocardial tissue regeneration in vivo. [ABSTRACT FROM AUTHOR]

Skeletal muscle trauma such as fracture or crush injury can result in a life‐threatening condition called acute compartment syndrome (ACS), which involves elevated compartmental pressure within a closed osteo‐fascial compartment, leading to collapse of the microvasculature and resulting in necrosis of the tissue due to ischemia. Diagnosis of ACS is complex and controversial due to the lack of standardized objective methods, which results in high rates of misdiagnosis/late diagnosis, leading to permanent neuro‐muscular damage. ACS pathophysiology is poorly understood at a cellular level due to the lack of physiologically relevant models. In this context, microfluidics organ‐on‐chip systems (OOCs) provide an exciting opportunity to investigate the cellular mechanisms of microvascular dysfunction that leads to ACS. In this article, the state‐of‐the‐art OOCs designs and strategies used to investigate microvasculature dysfunction mechanisms is reviewed. The differential effects of hemodynamic shear stress on endothelial cell characteristics such as morphology, permeability, and inflammation, all of which are altered during microvascular dysfunction is highlighted. The article then critically reviews the importance of microfluidics to investigate closely related microvascular pathologies that cause ACS. The article concludes by discussing potential biomarkers of ACS with a special emphasis on glycocalyx and providing a future perspective. [ABSTRACT FROM AUTHOR]

Background: Low-density lipoprotein cholesterol (LDL-C) is acknowledged as an independent risk factor (IRF) for atherosclerotic cardiovascular disease. Nevertheless, studies on the impact of LDL-C on microvasculature are still scarce. The retina, abundant in microvasculature, can now be examined for microvascular alterations through the novel, non-invasive, and quantitative optical coherence tomography angiography (OCTA) technique. Methods: In this cross-sectional study, 243 patients from the geriatric department were recruited (between December 2022 and December 2023). Individuals were classified into four groups based on their LDL-C levels: Group 1 (≤ 1.8 mmol/L), Group 2 (> 1.8 mmol/L to ≤ 2.6 mmol/L), Group 3 (> 2.6 mmol/L to ≤ 3.4 mmol/L), and Group 4 (> 3.4 mmol/L). The OCTA results including retinal vessel density (VD), foveal avascular zone (FAZ) area, macula thickness, and retinal nerve fiber layer (RNFL) thickness were contrasted across these groups. T-tests, analysis of variance, Welch's tests, or rank-sum tests were employed for statistical comparisons. In cases where significant differences between groups were found, post-hoc multiple comparisons or rank-sum tests were performed for pairwise group comparisons. Spearman's correlation coefficient was employed to perform bivariate correlation analysis to evaluate the relationship between LDL-C levels and various OCTA measurements. Multivariable regression analysis was used to evaluate the association between LDL-C levels and various OCTA measurements. Linear regression analysis or mixed-effects linear models were applied. Results: It was discovered that individuals with LDL-C levels exceeding 2.6 mmol/L (Groups 3 and 4) exhibited reduced VD in the retina, encompassing both the optic disc and macular regions, compared to those with LDL-C levels at or below 2.6 mmol/L (Groups 1 and 2). A negative correlation among LDL-C levels and retinal VD was identified, with r values spanning from − 0.228 to -0.385. Further regression analysis presented β values between − 0.954 and − 2.378. Additionally, no notable disparities were detected among the groups regarding FAZ area, macular thickness, and RNFL thickness. Conclusions: The outcomes of this study suggest that elevated LDL-C levels constitute an IRF for decreased VD across the entire retina. Trial registration: NCT05644548, December 1, 2022. [ABSTRACT FROM AUTHOR]

Aim: We aimed to test the hypothesis that a high‐salt diet (HS) impairs NO signaling in kidney microvascular endothelial cells through a histone deacetylase 1 (HDAC1)‐dependent mechanism. Methods: Male Sprague Dawley rats were fed normal salt diet (NS; 0.49% NaCl) or HS (4% NaCl) for 2 weeks. NO signaling was assessed by measuring L‐NAME induced vasoconstriction of the afferent arteriole using the blood perfused juxtamedullary nephron (JMN) preparation. In this preparation, kidneys were perfused with blood from a donor rat on a matching or different diet to that of the kidney donor. Kidney endothelial cells were isolated with magnetic activated cell sorting and HDAC1 activity was measured. Results: We found HS‐induced impaired NO signaling in the afferent arteriole. This was restored by inhibition of HDAC1 with MS‐275. Consistent with these findings, HDAC1 activity was increased in kidney endothelial cells. We further found the loss of NO to be dependent upon the diet of the blood donor rather than the diet of the kidney donor and the plasma from HS‐fed rats to be sufficient to induce impaired NO signaling. This indicates the presence of a humoral factor we termed plasma‐derived endothelial dysfunction mediator (PDEM). Pretreatment with the antioxidants, PEG‐SOD and PEG‐catalase, as well as the NOS cofactor, tetrahydrobiopterin, restored NO signaling. Conclusion: We conclude that HS activates endothelial HDAC1 through PDEM leading to decreased NO signaling. This study provides novel insights into the molecular mechanisms by which a HS decreases renal microvascular endothelial NO signaling. [ABSTRACT FROM AUTHOR]

Microvascular changes are considered key factors in the process of intervertebral disk degeneration (IDD). Microvascular invasion and growth into the nucleus pulposus (NP) and cartilaginous endplates are unfavorable factors that trigger IDD. In contrast, the rich distribution of microvessels in the bony endplates and outer layers of the annulus fibrosus is an important safeguard for the nutrient supply and metabolism of the intervertebral disk (IVD). In particular, the adequate supply of microvessels in the bony endplates is the main source of the nutritional supply for the entire IVD. Microvessels can affect the progression of IDD through a variety of pathways. Many studies have explored the effects of microvessel alterations in the NP, annulus fibrosus, cartilaginous endplates, and bony endplates on the local microenvironment through inflammation, apoptosis, and senescence. Studies also elucidated the important roles of microvessel alterations in the process of IDD, as well as conducted in‐depth explorations of cytokines and biologics that can inhibit or promote the ingrowth of microvessels. Therefore, the present manuscript reviews the published literature on the effects of microvascular changes on IVD to summarize the roles of microvessels in IVD and elaborate on the mechanisms of action that promote or inhibit de novo microvessel formation in IVD.

Abstract Background Low-density lipoprotein cholesterol (LDL-C) is acknowledged as an independent risk factor (IRF) for atherosclerotic cardiovascular disease. Nevertheless, studies on the impact of LDL-C on microvasculature are still scarce. The retina, abundant in microvasculature, can now be examined for microvascular alterations through the novel, non-invasive, and quantitative optical coherence tomography angiography (OCTA) technique. Methods In this cross-sectional study, 243 patients from the geriatric department were recruited (between December 2022 and December 2023). Individuals were classified into four groups based on their LDL-C levels: Group 1 (≤ 1.8 mmol/L), Group 2 (> 1.8 mmol/L to ≤ 2.6 mmol/L), Group 3 (> 2.6 mmol/L to ≤ 3.4 mmol/L), and Group 4 (> 3.4 mmol/L). The OCTA results including retinal vessel density (VD), foveal avascular zone (FAZ) area, macula thickness, and retinal nerve fiber layer (RNFL) thickness were contrasted across these groups. T-tests, analysis of variance, Welch’s tests, or rank-sum tests were employed for statistical comparisons. In cases where significant differences between groups were found, post-hoc multiple comparisons or rank-sum tests were performed for pairwise group comparisons. Spearman’s correlation coefficient was employed to perform bivariate correlation analysis to evaluate the relationship between LDL-C levels and various OCTA measurements. Multivariable regression analysis was used to evaluate the association between LDL-C levels and various OCTA measurements. Linear regression analysis or mixed-effects linear models were applied. Results It was discovered that individuals with LDL-C levels exceeding 2.6 mmol/L (Groups 3 and 4) exhibited reduced VD in the retina, encompassing both the optic disc and macular regions, compared to those with LDL-C levels at or below 2.6 mmol/L (Groups 1 and 2). A negative correlation among LDL-C levels and retinal VD was identified, with r values spanning from − 0.228 to -0.385. Further regression analysis presented β values between − 0.954 and − 2.378. Additionally, no notable disparities were detected among the groups regarding FAZ area, macular thickness, and RNFL thickness. Conclusions The outcomes of this study suggest that elevated LDL-C levels constitute an IRF for decreased VD across the entire retina. Trial registration NCT05644548, December 1, 2022.

Abstract Coagulopathy, microvascular alterations and concomitant organ dysfunctions are hallmarks of sepsis. Attempts to attenuate coagulation activation with an inhibitor of tissue factor (TF), i.e. tissue factor pathway inhibitor (TFPI), revealed no survival benefit in a heterogenous group of sepsis patients, but a potential survival benefit in patients with an international normalized ratio (INR)

Evaluation of retinal macular oxygen saturation in healthy controls can aid in understanding the pathological changes seen in similar locations of those with vascular diseases like diabetes. The aim of this study was to determine the test-retest repeatability of localised retinal oximetry measurements in the macula on the Zilia Oximeter within healthy subjects of different races, 18–40 years old. Oxygen saturation was measured between three time points within the same locations of the right eye. Twenty seven subjects were included (aged 26.3 ± 3.6 years). All were confirmed to have healthy retinas and at least 6/9 vision. Oximetry measurements were taken using the Zilia to acquire local oxygen saturation measurements (300 µm diameter) at four points 3.1 degrees from the fovea in the superior/temporal, superior/nasal, inferior/temporal, and inferior/nasal locations. Oximetry measurements were taken twice on the same day 20 minutes apart and then again 1–2 weeks later. Oximetry data was analysed with intraclass correlation between visits. To assess intrasubject repeatability, the Bland-Altman repeatability coefficient and coefficient of variation were calculated. Average Intraclass correlation for the three acquisition times of the right eye was 0.78. The averaged intrasubject repeatability coefficient for the three acquisition times was 8.4. The averaged coefficient of variation was 5.4%. The Zilia oximeter has good macular test-retest repeatability; however, multiple measurements may be needed to ensure accuracy. [ABSTRACT FROM AUTHOR]

An increasing body of evidence suggests a pivotal role for the microvasculature in the development of cardiovascular disease. A dysfunctional coronary microvascular network, specifically within endothelial cells—the inner most cell layer of vessels—is considered a strong, independent risk factor for future major adverse cardiac events. However, challenges exist with evaluating this critical vascular bed, as many of the currently available techniques are highly invasive and cost prohibitive. The more easily accessible peripheral microcirculation has surfaced as a potential surrogate in which to study mechanisms of coronary microvascular dysfunction and likewise may be used to predict poor cardiovascular outcomes. In this review, we critically evaluate a variety of prognostic, physiological, and mechanistic studies in humans to answer whether the peripheral microcirculation can add insight into coronary microvascular health. A conceptual framework is proposed that the health of the endothelium specifically may link the coronary and peripheral microvascular beds. This is supported by evidence showing a correlation between human coronary and peripheral endothelial function in vivo. Although not a replacement for investigating and understanding coronary microvascular function, the microvascular endothelium from the periphery responds similarly to (patho)physiological stress and may be leveraged to explore potential therapeutic pathways to mitigate stress-induced damage. [Display omitted] • Peripheral microvascular endothelial dysfunction has emerged as a strong independent predictor of poor cardiovascular outcomes. • For the special issue on Microvessels in the Heart , we pose the question of whether peripheral microvessels can be leveraged to answer key questions regarding coronary endothelial health. • Finally, we explore the endothelium as the potential link between the coronary and endothelial vascular beds and identify remaining important and unanswered questions. [ABSTRACT FROM AUTHOR]

Objective: Evaluation of tumor microvascular morphology is of great significance in tumor diagnosis, therapeutic effect prediction, and surgical planning. Recently, two-dimensional ultrasound localization microscopy (2DULM) has demonstrated its superiority in the field of microvascular imaging. However, it suffers from planar dependence and is unintuitive. We propose a novel three-dimensional ultrasound localization microscopy (3DULM) to avoid these limitations. Methods: We investigated 3DULM based on a 2D array for tumor microvascular imaging. After intravenous injection of contrast agents, all elements of the 2D array transmit and receive signals to ensure a high and stable frame rate. Microbubble signal extraction, filtering, positioning, tracking, and other processing were used to obtain a 3D vascular map, flow velocity, and flow direction. To verify the effectiveness of 3DULM, it was validated on double helix tubes and rabbit VX2 tumors. Cisplatin was used to verify the ability of 3DULM to detect microvascular changes during tumor treatment. Results: In vitro, the sizes measured by 3DULM at 3 mm and 13 mm were 178 μ m and 182 μ m , respectively. In the rabbit tumors, we acquired 9000 volumes to reveal vessels about 30 μ m in diameter, which surpasses the diffraction limit of ultrasound in traditional ultrasound imaging, and the results matched with micro-angiography. In addition, there were significant changes in vascular density and curvature between the treatment and control groups. Conclusions: The effectiveness of 3DULM was verified in vitro and in vivo. Hence, 3DULM may have potential applications in tumor diagnosis, tumor treatment evaluation, surgical protocol guidance, and cardiovascular disease. Clinical relevance statement: 3D ultrasound localization microscopy is highly sensitive to microvascular changes; thus, it has clinical potential for tumor diagnosis and treatment evaluation. Key Points: • 3D ultrasound localization microscopy is demonstrated on double helix tubes and rabbit VX2 tumors. • 3D ultrasound localization microscopy can reveal vessels about 30 μ m in diameter—far smaller than traditional ultrasound. • This form of imaging has potential applications in tumor diagnosis, tumor treatment evaluation, surgical protocol guidance, and cardiovascular disease. [ABSTRACT FROM AUTHOR]

Objective: Diffusion-weighted MRI is a technique that can infer microstructural and microcirculatory features from biological tissue, with particular application to renal tissue. There is extensive literature on diffusion tensor imaging (DTI) of anisotropy in the renal medulla, intravoxel incoherent motion (IVIM) measurements separating microstructural from microcirculation effects, and combinations of the two. However, interpretation of these features and adaptation of more specific models remains an ongoing challenge. One input to this process is a whole organ distillation of corticomedullary contrast of diffusion metrics, as has been explored for other renal biomarkers. Materials and methods: In this work, we probe the spatial dependence of diffusion MRI metrics with concentrically layered segmentation in 11 healthy kidneys at 3 T. The metrics include those from DTI, IVIM, a combined approach titled "REnal Flow and Microstructure AnisotroPy (REFMAP)", and a multiply encoded model titled "FC-IVIM" providing estimates of fluid velocity and branching length. Results: Fractional anisotropy decreased from the inner kidney to the outer kidney with the strongest layer correlation in both parenchyma (including cortex and medulla) and medulla with Spearman correlation coefficients and p-values (r, p) of (0.42, <0.001) and (0.37, <0.001), respectively. Also, dynamic parameters derived from the three models significantly decreased with a high correlation from the inner to the outer parenchyma or medulla with (r, p) ranges of (0.46–0.55, <0.001). Conclusions: These spatial trends might find implications for indirect assessments of kidney physiology and microstructure using diffusion MRI. [ABSTRACT FROM AUTHOR]

The microvasculature, which makes up the majority of the cardiovascular system, plays a crucial role in the process of thrombosis, with the pathological formation of blood clots inside blood vessels. Since blood microflow conditions significantly influence platelet activation and thrombosis, accurately mimicking the structure of bifurcating microvascular networks and emulating local physiological blood flow conditions are valuable for understanding blood clot formation. In this work, we present an in vitro model for blood clotting in microvessels, focusing on 3D bifurcations that align with Murray's law, which guides vascular networks by maintaining a constant wall shear rate throughout. Using these models, we demonstrate that microvascular bifurcations act as sites facilitating thrombus formation compared to straight models. Additionally, by culturing endothelial cells on the luminal surfaces of the models, we show the potential of using our in vitro platforms to recapitulate the initial clotting in diseases involving endothelial dysfunction, such as Thrombotic Thrombocytopenic Purpura. [ABSTRACT FROM AUTHOR]

Endothelial programmed death‐ligand 1 (PD‐L1) expression is higher in tumors than in normal tissues. Also, tumoral vasculatures tend to be leakier than normal vessels leading to a higher trans‐endothelial or transmural fluid flow. However, it is not clear whether such elevated transmural flow can control endothelial PD‐L1 expression. Here, a new microfluidic device is developed to investigate the relationship between transmural flow and PD‐L1 expression in microvascular networks (MVNs). After treating the MVNs with transmural flow for 24 h, the expression of PD‐L1 in endothelial cells is upregulated. Additionally, CD8 T cell activation by phytohemagglutinin (PHA) is suppressed when cultured in the MVNs pre‐conditioned with transmural flow. Moreover, transmural flow is able to further increase PD‐L1 expression in the vessels formed in the tumor microenvironment. Finally, by utilizing blocking antibodies and knock‐out assays, it is found that transmural flow‐driven PD‐L1 upregulation is controlled by integrin αVβ3. Overall, this study provides a new biophysical explanation for high PD‐L1 expression in tumoral vasculatures. [ABSTRACT FROM AUTHOR]

The capabilities of spectroscopy with spatial resolution when determining the optical properties and parameters of the microvasculature of the circulatory system of surface tissues are demonstrated using specific examples of recording and processing the spectral-spatial profiles of local diffuse reflection of light by tissues of the human hand. The heterogeneity of tissue properties caused by individual distribution of vessels and chromophore concentration gradients at the investigated point of the body in addition to inadequacies of the used calculation model due to poorly studied absorption indices of the main chromophores of exsanguinated and dehydrated subcutaneous tissue are shown to contribute most to the scatter of the obtained results. A technique for recording spectral-spatial profiles and their two-stage processing is presented. Its capabilities and disadvantages are discussed. Prospective application of diffuse reflectance spectroscopy with spatial resolution to controlling the hydration of surface tissues during treatment of their inflammation and edema is shown. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To describe the microvascular anatomy of the equine hind limb suspensory ligament. ANIMALS: 18 hind limbs harvested from 9 adult horses euthanized for reasons unrelated to lameness. METHODS: A catheter was placed in the transected cranial tibial artery at the level of the mid-distal tibia for each hind limb and used to inject 120 to 150 mL of contrast medium (2 limbs) to identify principal vasculature using contrast-enhanced CT or India ink (11 limbs) to identify microvasculature using the Spalteholz tissue-clearing technique. Routine histologic evaluation was performed on transverse sections from 4 hind limbs. RESULTS: The hind limb suspensory ligament is principally supplied by branches of the medial and lateral plantar metatarsal arteries and, to a lesser extent, the medial and lateral plantar arteries as well as the associated proximal and distal deep plantar arches. A uniformly distributed intraligamentous microvascular supply was observed without relative deficiencies in vascularity between the proximal, midbody, and distal regions. Histologic examination supported these findings, demonstrating a network of connective tissue surrounding and entering the suspensory ligament containing cross-sections of branches of the principal vasculature. CLINICAL RELEVANCE: The equine hind limb suspensory ligament has a uniformly distributed and abundant microvascular supply throughout its length, with no evidence of relative deficiency of vascular supply in any region. A region of hypovascularity does not appear to be a viable explanation for the high rate of injury to and commonality of lameness associated with the proximal hind suspensory ligament in horses. [ABSTRACT FROM AUTHOR]

The Achilles tendon (AT) is reportedly the most vulnerable to rupture at the midportion, a section of relative hypovascularity. It has been postulated that the twisted structure of this tendon may constitute a critical factor contributing to increased propensity to vascular compromise, decreased regenerative capacity, and rupture in the midsection of the AT. In this review, we will give an overview of the most relevant research on AT vasculature and twist, and delve into the interplay between the two elements in the context of AT disorders. The pertinent body of research suggests a considerable variability in tendon twist among individuals, which likely constitutes a determining factor in the extent to which vessels coursing along and between AT fibres are compressed during contraction-induced elongation of the tendon. Consequently, further research is necessary to investigate the precise association between tendon torsion and blood flow within the AT [ABSTRACT FROM AUTHOR]

Tumor structure is heterogeneous and complex, and it is difficult to obtain complete characteristics by two‐dimensional analysis. The aim of this study was to visualize and characterize volumetric vascular information of clear cell renal cell carcinoma (ccRCC) tumors using whole tissue phenotyping and three‐dimensional light‐sheet microscopy. Here, we used the diagnosing immunolabeled paraffin‐embedded cleared organs pipeline for tissue clearing, immunolabeling, and three‐dimensional imaging. The spatial distributions of CD34, which targets blood vessels, and LYVE‐1, which targets lymphatic vessels, were examined by calculating three‐dimensional density, vessel length, vessel radius, and density curves, such as skewness, kurtosis, and variance of the expression. We then examined those associations with ccRCC outcomes and genetic alteration state. Formalin‐fixed paraffin‐embedded tumor samples from 46 ccRCC patients were included in the study. Receiver operating characteristic curve analyses revealed the associations between blood vessel and lymphatic vessel distributions and pathological factors such as a high nuclear grade, large tumor size, and the presence of venous invasion. Furthermore, three‐dimensional imaging parameters stratified ccRCC patients regarding survival outcomes. An analysis of genomic alterations based on volumetric vascular information parameters revealed that PI3K‐mTOR pathway mutations related to the blood vessel radius were significantly different. Collectively, we have shown that the spatial elucidation of volumetric vasculature information could be prognostic and may serve as a new biomarker for genomic alterations. High‐end tissue clearing techniques and volumetric immunohistochemistry enable three‐dimensional analysis of tumors, leading to a better understanding of the microvascular structure in the tumor space. [ABSTRACT FROM AUTHOR]

Background: Little is known about alterations of the rotator cuff (RC) macroscopic vasculature associated with medical conditions and/or habits that predispose a person to diseases of the peripheral microcirculation. The high frequency of cuff tear and re-tear in patients with diabetes, hypercholesterolemia, uncontrolled arterial hypertension, or metabolic syndrome may be due to tissue hypovascularity. Methods: The macroscopic vasculature of both the articular and bursal sides of the posterosuperior RC was evaluated arthroscopically in 107 patients (mean age, 58.2 years) with no RC tear. Patients were divided into three groups according to medical comorbidities and lifestyle factors (group I, none; group II, smokers and/or drinkers and one comorbidity; and group III, two or more comorbidities). Pulsating vessels originating from both the myotendinous and osteotendinous junctions were assessed as "clearly evident," "poorly evident," or "not evident." Results: Groups I, II, and III comprised 36, 45, and 26 patients, respectively. Within the myotendinous junction, vessels were visualized in 22 group I patients (61%), 25 group II patients (55%), and 6 group III patients (23%) (P=0.007). Pulsating arterial vessels originating from the osteotendinous junction were seen in 42%, 36%, and 0% of patients, respectively (P<0.001). Within the bursal side of the RC, a dense anastomotic network was visualized (either clearly or poorly) in 94% (34), 80% (36), and 35% (9) of patients, respectively (P<0.001). Conclusions: The macroscopic vasculature of the RC is influenced by pre-existing diseases and lifestyle factors, which may impair peripheral microcirculation. Level of evidence: III. [ABSTRACT FROM AUTHOR]

The widespread adoption of glucagon‐like peptide‐1 (GLP‐1) agonists in treating type 2 diabetes mellitus (T2DM) and obesity has sparked investigations into their impact on hair health, an area characterized by diverse conjectures. Some propose potential risks such as disrupted hair growth cycles or premature androgenetic alopecia (AGA), while others suggest benefits linked to improved insulin sensitivity and enhanced scalp blood circulation. However, despite these theoretical underpinnings, clinical evidence linking GLP‐1 agonists to hair loss remains sparse. The necessity for vigilant patient monitoring and collaborative efforts cannot be overstressed in comprehensively addressing any potential consequences of GLP‐1 agonist therapy on hair health as their use continues to expand. [ABSTRACT FROM AUTHOR]

Background Little is known about alterations of the rotator cuff (RC) macroscopic vasculature associated with medical conditions and/or habits that predispose a person to diseases of the peripheral microcirculation. The high frequency of cuff tear and re-tear in patients with diabetes, hypercholesterolemia, uncontrolled arterial hypertension, or metabolic syndrome may be due to tissue hypovascularity. Methods The macroscopic vasculature of both the articular and bursal sides of the posterosuperior RC was evaluated arthroscopically in 107 patients (mean age, 58.2 years) with no RC tear. Patients were divided into three groups according to medical comorbidities and lifestyle factors (group I, none; group II, smokers and/or drinkers and one comorbidity; and group III, two or more comorbidities). Pulsating vessels originating from both the myotendinous and osteotendinous junctions were assessed as “clearly evident,” “poorly evident,” or “not evident.” Results Groups I, II, and III comprised 36, 45, and 26 patients, respectively. Within the myotendinous junction, vessels were visualized in 22 group I patients (61%), 25 group II patients (55%), and 6 group III patients (23%) (P=0.007). Pulsating arterial vessels originating from the osteotendinous junction were seen in 42%, 36%, and 0% of patients, respectively (P

Abstract Background Retinal microvascular signs are accessible measures of early alterations in microvascular dysregulation and have been associated with dementia; it is unclear if they are associated with AD (Alzheimer’s disease) pathogenesis as a potential mechanistic link. This study aimed to test the association of retinal microvascular abnormalities in mid and late life and late life cerebral amyloid. Methods Participants from the ARIC‐PET (Atherosclerosis Risk in Communities‐Positron Emission Tomography) study with a valid retinal measure (N = 285) were included. The associations of mid- and late-life retinal signs with late-life amyloid-β (Aβ) by florbetapir PET were tested. Two different measures of Aβ burden were included: (1) elevated amyloid (SUVR > 1.2) and (2) continuous amyloid SUVR. The retinal measures’ association with Aβ burden was assessed using logistic and robust linear regression models. A newly created retinal score, incorporating multiple markers of retinal abnormalities, was also evaluated in association with greater Aβ burden. Results Retinopathy in midlife (OR (95% CI) = 0.36 (0.08, 1.40)) was not significantly associated with elevated amyloid burden. In late life, retinopathy was associated with increased continuous amyloid standardized value uptake ratio (SUVR) (β (95%CI) = 0.16 (0.02, 0.32)) but not elevated amyloid burden (OR (95%CI) = 2.37 (0.66, 9.88)) when accounting for demographic, genetic and clinical risk factors. A high retinal score in late life, indicating a higher burden of retinal abnormalities, was also significantly associated with increased continuous amyloid SUVR (β (95% CI) = 0.16 (0.04, 0.32)) independent of vascular risk factors. Conclusions Retinopathy in late life may be an easily obtainable marker to help evaluate the mechanistic vascular pathway between retinal measures and dementia, perhaps acting via AD pathogenesis. Well-powered future studies with a greater number of retinal features and other microvascular signs are needed to test these findings.

Abstract Maintaining tissue perfusion in sepsis depends on vascular integrity provided by the endothelial glycocalyx, the critical layer covering the luminal surface of blood vessels. The glycocalyx is composed of proteoglycans, glycosaminoglycans, and functional plasma proteins that are critical for antithrombogenicity, regulating tone, controlling permeability, and reducing endothelial interactions with leukocytes and platelets. Degradation of the glycocalyx in sepsis is substantial due to thromboinflammation, and treatments for sepsis and septic shock may exacerbate endotheliopathy via additional glycocalyx injury. As a result, therapeutic strategies aimed at preserving glycocalyx integrity should be considered, including modifications in fluid volume resuscitation, minimizing catecholamine use, controlling hyperglycemia, and potential use of corticosteroids and anticoagulants. In this review, we explore treatment strategies aligned with the recommendations outlined in the Surviving Sepsis Campaign Guidelines 2021 with a special emphasis on evidence regarding glycocalyx protection.

Background: Retinal microvascular signs are accessible measures of early alterations in microvascular dysregulation and have been associated with dementia; it is unclear if they are associated with AD (Alzheimer's disease) pathogenesis as a potential mechanistic link. This study aimed to test the association of retinal microvascular abnormalities in mid and late life and late life cerebral amyloid. Methods: Participants from the ARIC‐PET (Atherosclerosis Risk in Communities‐Positron Emission Tomography) study with a valid retinal measure (N = 285) were included. The associations of mid- and late-life retinal signs with late-life amyloid-β (Aβ) by florbetapir PET were tested. Two different measures of Aβ burden were included: (1) elevated amyloid (SUVR > 1.2) and (2) continuous amyloid SUVR. The retinal measures' association with Aβ burden was assessed using logistic and robust linear regression models. A newly created retinal score, incorporating multiple markers of retinal abnormalities, was also evaluated in association with greater Aβ burden. Results: Retinopathy in midlife (OR (95% CI) = 0.36 (0.08, 1.40)) was not significantly associated with elevated amyloid burden. In late life, retinopathy was associated with increased continuous amyloid standardized value uptake ratio (SUVR) (β (95%CI) = 0.16 (0.02, 0.32)) but not elevated amyloid burden (OR (95%CI) = 2.37 (0.66, 9.88)) when accounting for demographic, genetic and clinical risk factors. A high retinal score in late life, indicating a higher burden of retinal abnormalities, was also significantly associated with increased continuous amyloid SUVR (β (95% CI) = 0.16 (0.04, 0.32)) independent of vascular risk factors. Conclusions: Retinopathy in late life may be an easily obtainable marker to help evaluate the mechanistic vascular pathway between retinal measures and dementia, perhaps acting via AD pathogenesis. Well-powered future studies with a greater number of retinal features and other microvascular signs are needed to test these findings. [ABSTRACT FROM AUTHOR]

The article discusses a study on the automation of retinal arterioles and venules segmentation in high-resolution fundus images using deep learning. The researchers created a new dataset of 240 manually segmented images and developed a deep learning model called LUNet for accurate segmentation. LUNet outperformed three benchmark algorithms on both local and external test sets, demonstrating its potential as a robust tool for diagnosing and understanding cardiovascular diseases through retinal imaging. The article highlights the importance of retinal microvasculature analysis and provides a valuable resource for further research in this field. The text also provides information about different datasets and their characteristics for the study of diabetic retinopathy, as well as details about the process of manual segmentation and the architecture of the deep learning algorithm used for segmentation. The given text discusses the performance of the deep learning algorithm, LUNet, for segmenting blood vessels in retinal images. LUNet achieved higher dice scores for arterioles and venules segmentation compared to other state-of-the-art algorithms and had comparable performance to an average junior annotator. The algorithm was also evaluated on external datasets and outperformed benchmark algorithms in terms of dice scores. Additionally, LUNet showed good performance in estimating vasculature biomarkers. The text discusses the development of a deep learning model called LUNet for the segmentation of venules and arterioles in fundus images. The model outperformed other benchmark algorithms and achieved high accuracy in segmenting [Extracted from the article]

Background: Electronic (e-) cigarettes are increasingly popular tobacco products on the US market. Traditional tobacco products are known to cause vascular dysfunction, one of the earliest indicators of cardiovascular disease (CVD) development. However, little is known about the effect of regular e-cigarette use on vascular function. The purpose of this study was to investigate the impact of regular e-cigarette use on vascular function and cardiovascular health in young, healthy adults. Methods: Twenty-one regular users of e-cigarettes (ECU) and twenty-one demographically matched non-users (NU) completed this study. Vascular health was assessed in the cutaneous microcirculation through different reactivity tests to evaluate overall functionality, endothelium-dependent vasodilation (EDD), and endothelium-independent vasodilation (EID). Macrovascular function was assessed using flow-mediated dilation (FMD). Results: Our results suggest that regular users of e-cigarettes present with premature microvascular impairment when compared to non-users. Specifically, they exhibit lower hyperemic (p = 0.003), thermal (p = 0.010), and EDD (p = 0.004) responses. No differences in EID between the groups were identified. We also identified that individuals who use e-cigarettes for longer than 3 years also present with systemic manifestations, as observed by significantly reduced macrovascular (p = 0.002) and microvascular (p ≤ 0.044) function. Conclusions: Our novel data suggests that young, apparently healthy, regular users of e-cigarettes present with premature vascular dysfunction in the microcirculation when compared to non-users. We have also identified systemic vascular dysfunction affecting both the micro and macrovasculature in those young individuals who used e-cigarettes for longer than 3 years. Taken together, these findings associate regular e-cigarette use with premature vascular dysfunctions and adverse cardiovascular outcomes. [ABSTRACT FROM AUTHOR]

Background/Aim: Probing brain tumor micro-vasculature holds significant importance in both basic cancer research and medical practice for tracking tumor development and assessing treatment outcomes. However, few imaging methods commonly used in clinics can noninvasively monitor the brain microvascular network at high precision and without exogenous contrast agents in vivo. The present study aimed to investigate the characteristics of microvasculature during brain tumor development in an orthotopic glioma mouse model. Materials and Methods: An orthotopic glioma mouse model was established by surgical orthotopic implantation of U87-MG-luc cells into the mouse brain. Then, optical coherence tomography angiography (OCTA) was utilized to characterize the microvasculature progression within 14 days. Results: The orthotopic glioma mouse model evaluated by bioluminescence imaging and MRI was successfully generated. As the tumor grew, the microvessels within the tumor area slowly decreased, progressing from the center to the periphery for 14 days. Conclusion: This study highlights the potential of OCTA as a useful tool to noninvasively visualize the brain microvascular network at high precision and without any exogenous contrast agents in vivo. [ABSTRACT FROM AUTHOR]

Fractional laser ablation is a technique developed in dermatology to induce remodeling of skin scars by creating a dense pattern of microinjuries. Despite remarkable clinical results, this technique has yet to be tested for scars in other tissues. As a first step toward determining the suitability of this technique, we aimed to (1) characterize the response to microinjuries in the healthy and cirrhotic liver, and (2) determine the underlying cause for any differences in response. Healthy and cirrhotic rats were treated with a fractional laser then euthanized from 0 h up to 14 days after treatment. Differential expression was assessed using RNAseq with a difference-in-differences model. Spatial maps of tissue oxygenation were acquired with hyperspectral imaging and disruptions in blood supply were assessed with tomato lectin perfusion. Healthy rats showed little damage beyond the initial microinjury and healed completely by 7 days without scarring. In cirrhotic rats, hepatocytes surrounding microinjury sites died 4-6 h after ablation, resulting in enlarged and heterogeneous zones of cell death. Hepatocytes near blood vessels were spared, particularly near the highly vascularized septa. Gene sets related to ischemia and angiogenesis were enriched at 4 h. Laser-treated regions had reduced oxygen saturation and broadly disrupted perfusion of nodule microvasculature, which matched the zones of cell death. Our results demonstrate that the cirrhotic liver has an exacerbated response to microinjuries and increased susceptibility to ischemia from microvascular damage, likely related to the vascular derangements that occur during cirrhosis development. Modifications to the fractional laser tool, such as using a femtosecond laser or reducing the spot size, may be able to prevent large disruptions of perfusion and enable further development of a laser-induced microinjury treatment for cirrhosis. [ABSTRACT FROM AUTHOR]

Maintaining tissue perfusion in sepsis depends on vascular integrity provided by the endothelial glycocalyx, the critical layer covering the luminal surface of blood vessels. The glycocalyx is composed of proteoglycans, glycosaminoglycans, and functional plasma proteins that are critical for antithrombogenicity, regulating tone, controlling permeability, and reducing endothelial interactions with leukocytes and platelets. Degradation of the glycocalyx in sepsis is substantial due to thromboinflammation, and treatments for sepsis and septic shock may exacerbate endotheliopathy via additional glycocalyx injury. As a result, therapeutic strategies aimed at preserving glycocalyx integrity should be considered, including modifications in fluid volume resuscitation, minimizing catecholamine use, controlling hyperglycemia, and potential use of corticosteroids and anticoagulants. In this review, we explore treatment strategies aligned with the recommendations outlined in the Surviving Sepsis Campaign Guidelines 2021 with a special emphasis on evidence regarding glycocalyx protection. [ABSTRACT FROM AUTHOR]

Introduction: The foot sole endures high magnitudes of pressure for sustained periods which results in transient but habitual cutaneous ischemia. Upon unloading, microvascular reactivity in cutaneous capillaries generates an influx of blood flow (PORH: post-occlusive reactive hyperemia). Whether pressure induced cutaneous ischemia from loading the foot sole impacts mechanoreceptor sensitivity remains unknown. Methods: Pressure induced ischemia was attained using a custom-built-loading device that applied load to the whole right foot sole at 2 magnitudes (15 or 50% body weight), for 2 durations (2 or 10 minutes) in thirteen seated participants. Mechanoreceptor sensitivity was assessed using Semmes-Weinstein monofilaments over the third metatarsal (3MT), medial arch (MA), and heel. Perceptual thresholds (PT) were determined for each site prior to loading and then applied repeatedly to a metronome to establish the time course to return to PT upon unload, defined as PT recovery time. Microvascular flux was recorded from an in-line laser speckle contrast imager (FLPI-2, Moor Instruments Inc.) to establish PORH peak and recovery rates at each site. Results: PT recovery and PORH recovery rate were most influenced at the heel and by load duration rather than load magnitude. PT recovery time at the heel was significantly longer with 10 minutes of loading, regardless of magnitude. Heel PORH recovery rate was significantly slower with 10minutes of loading. The 3MT PT recovery time was only longer after 10 minutes of loading at 50% body weight. Microvascular reactivity or sensitivity was not influenced with loading at the MA. A simple linear regression found that PORH recovery rate could predict PT recovery time at the heel (R2=0.184, p<0.001). Conclusion: In populations with degraded sensory feedback, such as diabetic neuropathy, the risk for ulcer development is heightened. Our work demonstrated that prolonged loading in healthy individuals can impair skin sensitivity, which highlights the risks of prolonged loading and is likely exacerbated in diabetes. Understanding the direct association between sensory function and microvascular reactivity in age and diabetes related nerve damage, could help detect early progressions of neuropathy and mitigate ulcer development. [ABSTRACT FROM AUTHOR]

Recently, a novel method to estimate wedge pressure (Pw)-corrected minimal microvascular resistance (MR) was introduced. However, this method has not been validated since, and there are some theoretical concerns regarding the impact of different physiological conditions on the derivation of Pw measurements. This study sought to validate the recently introduced method to estimate Pw-corrected MR in a Doppler-derived study population and to evaluate the impact of different physiological conditions on the Pw measurements and the derivation of Pw-corrected MR. The method to derive "estimated" hyperemic microvascular resistance (HMR) without the need for Pw measurements was validated by estimating the coronary fractional flow reserve (FFRcor) from myocardial fractional flow reserve (FFRmyo) in a Doppler-derived study population (N = 53). From these patients, 24 had hyperemic Pw measurements available for the evaluation of hyperemic conditions on the derivation of Pw and its effect on the derivation of both "true" (with measured Pw) and "estimated" Pw-corrected HMR. Nonhyperemic Pw differed significantly from Pw measured in hyperemic conditions (26 ± 14 vs. 35 ± 14 mmHg, respectively, P < 0.005). Nevertheless, there was a strong linear relationship between FFRcor and FFRmyo in nonhyperemic conditions (R2 = 0.91, P < 0.005), as well as in hyperemic conditions (R2 = 0.87, P < 0.005). There was a strong linear relationship between "true" HMR and "estimated" HMR using either nonhyperemic (R2 = 0.86, P < 0.005) or hyperemic conditions (R2 = 0.85, P < 0.005) for correction. In contrast to a modest agreement between nonhyperemic Pw-corrected HMR and apparent HMR (R2 = 0.67, P < 0.005), hyperemic Pw-corrected HMR showed a strong agreement with apparent HMR (R2 = 0.88, P < 0.005). We validated the calculation method for Pw-corrected MR in a Doppler velocity-derived population. In addition, we found a significant impact of hyperemic conditions on the measurement of Pw and the derivation of Pw-corrected HMR. NEW & NOTEWORTHY: The following are what is known: 1) wedge-pressure correction is often considered for the derivation of indices of minimal microvascular resistance, and 2) the Yong method for calculating wedge pressure-corrected index of microvascular resistance (IMR) without balloon inflation has never been validated in a Doppler-derived population and has not been tested under different physiological conditions. This study 1) adds validation for the Yong method for calculated wedge-pressure correction in a Doppler-derived study population and 2) shows significant influence of the physiological conditions on the derivation of coronary wedge pressure. [ABSTRACT FROM AUTHOR]

Context Vascular insulin resistance is commonly observed in obesity and diabetes; yet, insulin action across the vascular tree and the relationship between insulin responses at different vascular locations remains incompletely defined. Objective To elucidate the impact of elevated free fatty acids (FFAs) on insulin action across the arterial tree and define the relationship among insulin actions in the different arterial segments. Methods This randomized crossover study assigned healthy lean adults to 2 separate admissions with euglycemic insulin clamp superimposed for the final 120 minutes of 5-hour lipid or matched-volume saline infusion. Vascular measures including peripheral and central arterial blood pressure, brachial artery flow-mediated dilation (FMD), carotid femoral pulse wave velocity (cfPWV), augmentation index (AIx), pulse wave separation analysis, subendocardial viability ratio (SEVR), and skeletal and cardiac muscle microvascular perfusion were determined before and after insulin clamp. Insulin-mediated whole body glucose disposal was calculated. Results Insulin enhanced FMD, AIx, reflection magnitude, and cardiac and skeletal muscle microvascular perfusion. Elevation of plasma FFA concentrations to the levels seen in the postabsorptive state in people with insulin resistance suppressed SEVR, blunted insulin-induced increases in FMD and cardiac and skeletal muscle microvascular blood volume, and lowered insulin's ability to reduce AIx and reflection magnitude. In multivariate regression, insulin-mediated muscle microvascular perfusion was independently associated with insulin-mediated FMD and cfPWV. Conclusion Clinically relevant elevation of plasma FFA concentrations induces pan-arterial insulin resistance, the vascular insulin resistance outcomes are interconnected, and insulin-mediated muscle microvascular perfusion associates with cardiovascular disease predictors. Our data provide biologic plausibility whereby a causative relationship between FFAs and cardiovascular disease could exist, and suggest that further attention to interventions that block FFA-mediated vascular insulin resistance may be warranted. [ABSTRACT FROM AUTHOR]

Diabetes is not only an endocrine but also a vascular disease. Vascular defects are usually seen as consequence of diabetes. However, at the level of the pancreatic islet, vascular alterations have been described before symptom onset. Importantly, the cellular and molecular mechanisms underlying these early vascular defects have not been identified, neither how these could impact the function of islet endocrine cells. In this review, we will discuss the possibility that dysfunction of the mural cells of the microvasculature—known as pericytes—underlies vascular defects observed in islets in pre-symptomatic stages. Pericytes are crucial for vascular homeostasis throughout the body, but their physiological and pathophysiological functions in islets have only recently started to be explored. A previous study had already raised interest in the "microvascular" approach to this disease. With our increased understanding of the crucial role of the islet microvasculature for glucose homeostasis, here we will revisit the vascular aspects of islet function and how their deregulation could contribute to diabetes pathogenesis, focusing in particular on type 1 diabetes (T1D). [ABSTRACT FROM AUTHOR]

Our objective was to evaluate normative data for near‐infrared spectroscopy (NIRS) in 110 healthy volunteers by Fitzpatrick skin type (FST) and region of the foot. We obtained measurements of the dorsum and plantar foot using a commercially available device (SnapshotNIR, Kent Imaging, Calgary Canada). On the dorsum of the foot, people with FST6 had significantly lower oxygen saturation compared to FST1‐5 (p < 0.001), lower oxyhaemoglobin compared to FST2‐5 (p = 0.001), but there was no difference in deoxyhaemoglobin. No differences were found on the plantar foot. When comparing dorsal and plantar foot, there was higher oxyhaemoglobin (0.40 ± 0.09 vs. 0.51 ± 0.12, p < 0.001) and deoxyhaemoglobin (0.16 ± 0.05 vs. 0.21 ± 0.05, p < 0.001) on the plantar foot, but no differences in oxygen saturation (dorsal 70.7 ± 10.8, plantar 70.0 ± 9.5, p = 0.414). In 6.4% of feet, there were black areas, for which no NIRS measurements could be generated. All areas with no data were on the dorsal foot and only found in FST 5–6. People with FST6 had significantly larger areas with no data compared to FST 5 (22.2 cm2 ± 20.4 vs. 1.9 cm2 ± 0.90, p = 0.007). These findings should be considered when using NIRS technology. Skin pigmentation should be evaluated in future NIRS studies. [ABSTRACT FROM AUTHOR]

Abstract Tumor structure is heterogeneous and complex, and it is difficult to obtain complete characteristics by two‐dimensional analysis. The aim of this study was to visualize and characterize volumetric vascular information of clear cell renal cell carcinoma (ccRCC) tumors using whole tissue phenotyping and three‐dimensional light‐sheet microscopy. Here, we used the diagnosing immunolabeled paraffin‐embedded cleared organs pipeline for tissue clearing, immunolabeling, and three‐dimensional imaging. The spatial distributions of CD34, which targets blood vessels, and LYVE‐1, which targets lymphatic vessels, were examined by calculating three‐dimensional density, vessel length, vessel radius, and density curves, such as skewness, kurtosis, and variance of the expression. We then examined those associations with ccRCC outcomes and genetic alteration state. Formalin‐fixed paraffin‐embedded tumor samples from 46 ccRCC patients were included in the study. Receiver operating characteristic curve analyses revealed the associations between blood vessel and lymphatic vessel distributions and pathological factors such as a high nuclear grade, large tumor size, and the presence of venous invasion. Furthermore, three‐dimensional imaging parameters stratified ccRCC patients regarding survival outcomes. An analysis of genomic alterations based on volumetric vascular information parameters revealed that PI3K‐mTOR pathway mutations related to the blood vessel radius were significantly different. Collectively, we have shown that the spatial elucidation of volumetric vasculature information could be prognostic and may serve as a new biomarker for genomic alterations. High‐end tissue clearing techniques and volumetric immunohistochemistry enable three‐dimensional analysis of tumors, leading to a better understanding of the microvascular structure in the tumor space.

Abstract Endothelial programmed death‐ligand 1 (PD‐L1) expression is higher in tumors than in normal tissues. Also, tumoral vasculatures tend to be leakier than normal vessels leading to a higher trans‐endothelial or transmural fluid flow. However, it is not clear whether such elevated transmural flow can control endothelial PD‐L1 expression. Here, a new microfluidic device is developed to investigate the relationship between transmural flow and PD‐L1 expression in microvascular networks (MVNs). After treating the MVNs with transmural flow for 24 h, the expression of PD‐L1 in endothelial cells is upregulated. Additionally, CD8 T cell activation by phytohemagglutinin (PHA) is suppressed when cultured in the MVNs pre‐conditioned with transmural flow. Moreover, transmural flow is able to further increase PD‐L1 expression in the vessels formed in the tumor microenvironment. Finally, by utilizing blocking antibodies and knock‐out assays, it is found that transmural flow‐driven PD‐L1 upregulation is controlled by integrin αVβ3. Overall, this study provides a new biophysical explanation for high PD‐L1 expression in tumoral vasculatures.

Cardiovascular diseases, particularly ischemic heart disease, area leading cause of morbidity and mortality worldwide. Myocardial infarction (MI) results in extensive cardiomyocyte loss, inflammation, extracellular matrix (ECM) degradation, fibrosis, and ultimately, adverse ventricular remodeling associated with impaired heart function. While heart transplantation is the only definitive treatment for end-stage heart failure, donor organ scarcity necessitates the development of alternative therapies. In such cases, methods to promote endogenous tissue regeneration by stimulating growth factor secretion and vascular formation alone are insufficient. Techniques for the creation and transplantation of viable tissues are therefore highly sought after. Approaches to cardiac regeneration range from stem cell injections to epicardial patches and interposition grafts. While numerous preclinical trials have demonstrated the positive effects of tissue transplantation on vasculogenesis and functional recovery, long-term graft survival in large animal models is rare. Adequate vascularization is essential for the survival of transplanted tissues, yet pre-formed microvasculature often fails to achieve sufficient engraftment. Recent studies report success in enhancing cell survival rates in vitro via tissue perfusion. However, the transition of these techniques to in vivo models remains challenging, especially in large animals. This review aims to highlight the evolution of cardiac patch and stem cell therapies for the treatment of cardiovascular disease, identify discrepancies between in vitro and in vivo studies, and discuss critical factors for establishing effective myocardial tissue regeneration in vivo.

Ultrasound localization microscopy (ULM) has gained increasing attention in recent years because of its ability to visualize blood vessels at super-resolution. The field of oncology, in particular, could benefit from detailed vascular characterization, for example, for diagnosis and therapy monitoring. This study was aimed at refining ULM for breast cancer patients by optimizing the measurement protocol, identifying translational challenges and combining ULM and shear wave elastography. We computed ULM images of 11 patients with breast cancer by recording contrast-enhanced ultrasound (CEUS) sequences and post-processing them in an offline pipeline. For CEUS, two different doses and injection speeds of SonoVue were applied. The best injection protocol was determined based on quantitative parameters derived from so-called occurrence maps. In addition, a suitable measurement time window was determined, also considering the occurrence of motion. ULM results were compared with shear wave elastography and histological vessel density. At the higher dose and injection speed, the highest number of microbubbles, number of tracks and vessel coverage were achieved, leading to the most detailed representation of tumor vasculature. Even at the highest concentration, no significant overlay of microbubble signals occurred. Motion significantly reduced the number of usable frames, thus limiting the measurement window to 3.5 min. ULM vessel coverage was comparable to the histological vessel fraction and correlated significantly with mean tumor elasticity. The settings for microbubble injection strongly influence ULM images, thus requiring optimized protocols for different indications. Patient and examiner motion was identified as the main translational challenge for ULM. [ABSTRACT FROM AUTHOR]

The mammary gland is a highly vascularized organ influenced by sex hormones including estrogen (E2) and progesterone (P4). Beyond whole‐organism studies in rodents or cell monocultures, hormonal effects on the breast microvasculature remain largely understudied. Recent methods to generate 3D microvessels on‐chip have enabled direct observation of complex vascular processes; however, these models often use non‐tissue‐specific cell types, such as human umbilical vein endothelial cells (HUVECs) and fibroblasts from various sources. Here, novel mammary‐specific microvessels are generated by coculturing primary breast endothelial cells and fibroblasts under optimized culture conditions. These microvessels are mechanosensitive (to interstitial flow) and require endothelial–stromal interactions to develop fully perfusable vessels. These mammary‐specific microvessels are also responsive to exogenous stimulation by sex hormones. When treated with combined E2 and P4, corresponding to the four phases of the menstrual cycle (period, follicular, ovular, and luteal), vascular remodeling and barrier function are altered in a phase‐dependent manner. The presence of high E2 (ovulation) promotes vascular growth and remodeling, corresponding to high depletion of proangiogenic factors, whereas high P4 concentrations (luteal) promote vascular regression. The effects of combined E2 and P4 hormones are not only dose‐dependent but also tissue‐specific, as are shown by similarly treating non‐tissue‐specific HUVEC microvessels. [ABSTRACT FROM AUTHOR]

The study of aging and neurodegenerative processes in the human brain requires a comprehensive understanding of cytoarchitectonic, myeloarchitectonic, and vascular structures. Recent computational advances have enabled volumetric reconstruction of the human brain using thousands of stained slices, however, tissue distortions and loss resulting from standard histological processing have hindered deformation‐free reconstruction. Here, the authors describe an integrated serial sectioning polarization‐sensitive optical coherence tomography (PSOCT) and two photon microscopy (2PM) system to provide label‐free multi‐contrast imaging of intact brain structures, including scattering, birefringence, and autofluorescence of human brain tissue. The authors demonstrate high‐throughput reconstruction of 4 × 4 × 2cm3 sample blocks and simple registration between PSOCT and 2PM images that enable comprehensive analysis of myelin content, vascular structure, and cellular information. The high‐resolution 2PM images provide microscopic validation and enrichment of the cellular information provided by the PSOCT optical properties on the same sample, revealing the densely packed fibers, capillaries, and lipofuscin‐filled cell bodies in the cortex and white matter. It is shown that the imaging system enables quantitative characterization of various pathological features in aging process, including myelin degradation, lipofuscin accumulation, and microvascular changes, which opens up numerous opportunities in the study of neurodegenerative diseases in the future. [ABSTRACT FROM AUTHOR]

To evaluate the retinal and choroidal microvasculature after one or two horizontal rectus muscle surgeries in strabismus patients using swept-source optical coherence tomography angiography (SS-OCTA). 30 eyes of 26 patients who underwent horizontal rectus muscle surgery were included in this study. Group A, A' and Group B , B' respectively consisted preoperative and postoperative measurements of patients who underwent one or two horizontal rectus muscle surgeries. We analyzed the vessel density (VD) of the superficial vascular complex (SVC), the deep vascular complex (DVC), the choriocapillary layer (CC), choroidal vascular index (CVI), choroidal thickness (T-Ch) and retinal nerve fiber layer thickness (T-RNFL) preoperatively, and one week postoperatively. Only in the nasal sector of the perifoveal zone, the VD in SVC demonstrated a significant increase in Group A' (p = 0.027). There was a statistically significant difference in the VD changes of SVC between Group A and Group B (p = 0.043). The VD in DVC did not change significantly in the whole macular compared with the preoperative. Moreover, in both Group A' and Group B', the VD in CC showed a reduction in a single sector of the parafoveal area (p < 0.05). Group A' have increased CVI in the nasal sector of the perifoveal region (p = 0.008). In addition, the T-Ch increase in the perifoveal region was more significant in Group B' than in Group A' (p < 0.05). Group A' showed statistically significant decreases in T-RNFL in the foveal and parafoveal regions (p < 0.05). This study revealed that the increase in choroidal thickness was more significant after two rectus muscle surgery. In addition, there were microvascular changes in sectional macular regions after strabismus surgery. OCTA is an excellent way to study the impact of strabismus surgery on the macular structure and blood flow. We used SS-OCTA, which provided more objective and accurate measurements, to assess macular vessel density and thickness of retinal and choroid after one or two horizontal rectus muscle surgeries. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to investigate the effects of neonatal hypoxic– ischemic brain damage (HIBD) on early-stage neuro-motor function, cerebral blood flow, and the neurovascular unit. Methods: Twenty-four Sprague–Dawley newborn rats aged 7 days were obtained and randomly assigned to either the sham or the model group using a random number table. The HIBD model was established using the Rice-Vannucci method. After the induction of HIBD, the body weight of the rats was measured and their neuro-motor function was assessed. Further, cerebral blood flow perfusion was evaluated using laser speckle flow imaging, and immunofluorescent staining techniques were employed for examining the activation of specific markers and their morphological changes in different cell populations, which included vascular endothelial cells, neurons, astrocytes, and microglia within the motor cortex. Results: After HIBD, the model group exhibited impaired neuro-motor function and growth. Cerebral blood flow perfusion decreased in both the hemispheres on day 1 and in the ipsilateral brain on day 4. However, no significant difference was observed between the two groups on day 7. Moreover, the CD31 and NeuN showed a sharp decline on day 1, which was followed by a gradual increase in the expression levels. The activated microglia and astrocytes formed clusters in the injured cortex. Notably, the regions with positive staining for Arg-1, Iba1, CD68, and GFAP consistently displayed higher values in the model group as compared to that in the sham group. The total number of branch endpoints and microglia branches was higher in the model group than in the sham group. Immunofluorescent co-localization analysis revealed no co-staining between Iba-1 and Arg-1; however, the Pearson’s R-value for the co-localization of Iba-1 and CD68 was higher in the model group, which indicated an increasing trend of co-staining in the model group. Conclusion: Early-stage neuro-motor function, cerebral blood flow, microvasculature, and neurons in neonatal rats exhibited a trend of gradual recovery over time. The activation and upregulation of neuroglial cells continued persistently after HIBD. Furthermore, the impact of HIBD on early-stage neuromotor function in newborn rats did not synchronize with the activation of neuroglial cells. The recovery of neuro-motor function, microvasculature, and neurons occurred earlier than that of neuroglial cells. [ABSTRACT FROM AUTHOR]

Moderate-to-heavy episodic ("binge") drinking is the most common form of alcohol consumption in the United States. Alcohol at binge drinking concentrations reduces brain artery diameter in vivo and in vitro in many species including rats, mice, and humans. Despite the critical role played by brain vessels in maintaining neuronal function, there is a shortage of methodologies to simultaneously assess neuron and blood vessel function in deep brain regions. Here, we investigate cerebrovascular responses to ethanol by choosing a deep brain region that is implicated in alcohol disruption of brain function, the hippocampal CA1, and describe the process for obtaining simultaneous imaging of pyramidal neuron activity and diameter of nearby microvessels in freely moving mice via a dualcolor miniscope. Recordings of neurovascular events were performed upon intraperitoneal injection of saline versus 3 g/kg ethanol in the same mouse. In male mice, ethanol mildly increased the amplitude of calcium signals while robustly decreasing their frequency. Simultaneously, ethanol decreased microvessel diameter. In females, ethanol did not change the amplitude or frequency of calcium signals from CA1 neurons but decreased microvessel diameter. A linear regression of ethanol-induced reduction in number of active neurons and microvessel constriction revealed a positive correlation (R = 0.981) in females. Together, these data demonstrate the feasibility of simultaneously evaluating neuronal and vascular components of alcohol actions in a deep brain area in freely moving mice, as well as the sexual dimorphism of hippocampal neurovascular responses to alcohol. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To investigate the effects of hemorrhagic shock and fresh whole blood resuscitation on the microcirculation and endothelial glycocalyx using sidestream dark field (SDF) imaging and plasma biomarkers. ANIMALS: 8 purpose-bred dogs. METHODS: Pressure-targeted hemorrhagic shock was induced in anesthetized dogs. SDF measurement of perfused boundary region and microcirculatory variables (RBC flow, total vessel density, and relative and absolute capillary blood volume), biomarker measurement (heparan sulfate, hyaluronan, VE-cadherin, and syndecan-1), mean arterial blood pressure, and cardiac output measurement were performed before anesthesia (TP0), after induction (TP1), after hemorrhagic shock (TP2), and after 50% retransfusion (TP3) and 100% retransfusion (TP4). RESULTS: At TP1, TP2, TP3, and TP4, mean arterial blood pressure was 74.25 ± 7.17 mm Hg, 49.50 ± 13.74 mm Hg, 63.50 ± 13.29 mm Hg, and 71.38 ± 8.77 mm Hg, and cardiac output was 2.57 ± 1.01 L/min, 0.8 ± 0.36 L/min, 1.81 ± 0.57 L/min, and 2.93 ± 1.22 L/min, respectively. Heparan sulfate, hyaluronan, syndecan-1, and VE-cadherin ranges were 24.80 to 77.72 ng/mL, 5.77 to 105.06 ng/mL, below detection to 1,545.69 pg/mL, and 0 to 2.52 ng/mL, respectively. Perfused boundary region, RBC flow, total vessel density, and relative and absolute capillary blood volume ranges were 1.75 to 2.68 µm, 89.6 to 584.5 µm/s, 51.7 to 1,914.3 mm/m², 0.94 to 1.53 10³ µm³, and 1.50 to 94.30 10³ µm³, respectively. Heparan sulfate decreased significantly over time (P = .016). No significant differences were found for microcirculatory variables, perfused boundary regions, or other biomarkers. CLINICAL RELEVANCE: This was the first study to assess microvascular dysfunction and endothelial shedding in a canine hemorrhagic shock model using SDF microscopy (Glycocheck) and plasma biomarkers. Further studies are needed to determine clinical relevance. [ABSTRACT FROM AUTHOR]