Vascular-related Diseases Research Articles

Potential Effects of Natural H2S-Donors in Hypertension Management.

After the discovery of hydrogen sulfide (H2S) in the central nervous system by Abe and Kimura in 1996, the physiopathological role of H2S has been widely investigated in several systems such as the cardiovascular. In particular, H2S plays a pivotal role in the control of vascular tone, exhibiting mechanisms of action able to induce vasodilation: for instance, activation of potassium channels (KATP and Kv7) and inhibition of 5-phosphodiesterase (5-PDE). These findings paved the way for the research of natural and synthetic exogenous H2S-donors (i.e., molecules able to release H2S) in order to have new tools for the management of hypertension. In this scenario, some natural molecules derived from Alliaceae (i.e., garlic) and Brassicaceae (i.e., rocket or broccoli) botanical families show the profile of slow H2S-donors able to mimic the endogenous production of this gasotransmitter and therefore can be viewed as interesting potential tools for management of hypertension or pre-hypertension. In this article, the preclinical and clinical impacts of these natural H2S-donors on hypertension and vascular integrity have been reviewed in order to give a complete panorama of their potential use for the management of hypertension and related vascular diseases.

Reactive Oxygen Species and Oxidative Stress in Vascular-Related Diseases

Oxidative stress (OS) refers to the enhancement of oxidation and the decreased of related antioxidant enzymes activity under pathological conditions, resulting in relatively excess reactive oxygen species (ROS), causing cytotoxicity, which leads to tissue damage and is linked to neurodegenerative diseases, cardiovascular diseases, diabetes, cancers, and many other pathologies. As an important intracellular signaling molecule, ROS can regulate numerous physiological actions, such as vascular reactivity and neuronal function. According to several studies, the uncontrolled production of ROS is related to vascular injury. The growing evidence revealing how traditional risk factors translate into ROS and lead to vasculitis and other vascular diseases. In this review, we sought to mainly discuss the role of ROS and antioxidant mechanisms in vascular-related diseases, especially cardiovascular and common macrovascular diseases.

Sphingosine 1-phosphate and its regulatory role in vascular endothelial cells.

Sphingosine 1-phosphate (S1P) is a bioactive metabolite of sphingomyelin. S1P activates a series of signaling cascades by acting on its receptors S1PR1-3 on endothelial cells (ECs), which plays an important role in endothelial barrier maintenance, anti-inflammation, antioxidant and angiogenesis, and thus is considered as a potential therapeutic biomarker for ischemic stroke, sepsis, idiopathic pulmonary fibrosis, cancers, type 2 diabetes and cardiovascular diseases. We presently review the levels of S1P in those vascular and vascular-related diseases. Plasma S1P levels were reduced in various inflammation-related diseases such as atherosclerosis and sepsis, but were increased in other diseases including type 2 diabetes, neurodegeneration, cerebrovascular damages such as acute ischemic stroke, Alzheimer's disease, vascular dementia, angina, heart failure, idiopathic pulmonary fibrosis, community-acquired pneumonia, and hepatocellular carcinoma. Then, we highlighted the molecular mechanism by which S1P regulated EC biology including vascular development and angiogenesis, inflammation, permeability, and production of reactive oxygen species (ROS), nitric oxide (NO) and hydrogen sulfide (H₂S), which might provide new ways for exploring the pathogenesis and implementing individualized therapy strategies for those diseases.

Multi-Trait Genome-Wide Association Study of Atherosclerosis Detects Novel Pleiotropic Loci.

Although affecting different arterial territories, the related atherosclerotic vascular diseases coronary artery disease (CAD) and peripheral artery disease (PAD) share similar risk factors and have shared pathobiology. To identify novel pleiotropic loci associated with atherosclerosis, we performed a joint analysis of their shared genetic architecture, along with that of common risk factors. Using summary statistics from genome-wide association studies of nine known atherosclerotic (CAD, PAD) and atherosclerosis risk factors (body mass index, smoking initiation, type 2 diabetes, low density lipoprotein, high density lipoprotein, total cholesterol, and triglycerides), we perform 15 separate multi-trait genetic association scans which resulted in 25 novel pleiotropic loci not yet reported as genome-wide significant for their respective traits. Colocalization with single-tissue eQTLs identified candidate causal genes at 14 of the detected signals. Notably, the signal between PAD and LDL-C at the PCSK6 locus affects PCSK6 splicing in human liver tissue and induced pluripotent derived hepatocyte-like cells. These results show that joint analysis of related atherosclerotic disease traits and their risk factors allowed identification of unified biology that may offer the opportunity for therapeutic manipulation. The signal at PCSK6 represent possible shared causal biology where existing inhibitors may be able to be leveraged for novel therapies.

Angiopoietin-2-induced lymphatic endothelial cell migration drives lymphangiogenesis via the β1 integrin-RhoA-formin axis.

Lymphangiogenesis is an essential physiological process but also a determining factor in vascular-related pathological conditions. Angiopoietin-2 (Ang2) plays an important role in lymphatic vascular development and function and its upregulation has been reported in several vascular-related diseases, including cancer. Given the established role of the small GTPase RhoA on cytoskeleton-dependent endothelial functions, we investigated the relationship between RhoA and Ang2-induced cellular activities. This study shows that Ang2-driven human dermal lymphatic endothelial cell migration depends on RhoA. We demonstrate that Ang2-induced migration is independent of the Tie receptors, but dependent on β1 integrin-mediated RhoA activation with knockdown, pharmacological approaches, and protein sequencing experiments. Although the key proteins downstream of RhoA, Rho kinase (ROCK) and myosin light chain, were activated, blockade of ROCK did not abrogate the Ang2-driven migratory effect. However, formins, an alternative target of RhoA, were identified as key players, and especially FHOD1. The Ang2-RhoA relationship was explored in vivo, where lymphatic endothelial RhoA deficiency blocked Ang2-induced lymphangiogenesis, highlighting RhoA as an important target for anti-lymphangiogenic treatments.

Abstract 13109: Epigenetic Regulation and Function of Pleiotropic GWAS Locus LRP1 in Human Induced Pluripotent Stem Cells Derived Contractile Smooth Muscle Cells

Introduction: Spontaneous coronary artery dissection (SCAD) is an increasingly recognized cause of myocardial infarction in young and middle-aged women. A common genetic variant, rs11172113, located in LRP1 (low density lipoprotein receptor-related protein 1) first intron, was associated with several vascular diseases, including SCAD, and regulation of LRP1 expression in arterial tissues. However, the biological mechanisms through which rs11172113 influence LRP1 function in the context of non-atherosclerotic arterial lesions are not known. Hypothesis: We hypothesized that rs11172113 genotype affects LRP1 expression through specific mechanisms in contractile smooth muscle cells (SMCs), leading to alterations of their physiological function. Methods: We differentiated 4 human induced pluripotent stem cells (iPSCs) lines (2 males, 2 females) towards either contractile or synthetic SMCs using a recently optimized 24-day protocol. We performed RNA-Seq and ATAC-Seq at 6 time points during differentiation. We silenced LRP1 using siRNAs in differentiated SMCs and used CRISPR-Cas9 to induce deletions of the enhancer region containing rs11172113 or frame-shift indels in exons 2 or 5 of LRP1 in iPSCs. Results: iPSCs derived SMCs presented the expected morphology and expression of SMC markers. Transcriptomic analyses showed that contractile SMCs harbored SMC properties during late differentiation and resembled SMCs of artery tissue, whereas genes involved in cell stress were upregulated in synthetic SMCs at the end of differentiation. In particular, LRP1 expression and DNA accessibility at rs11172113 were higher in contractile SMCs. The deletion of rs11172113 enhancer region led to a decrease in the expression of LRP1 in both contractile and synthetic SMCs. LRP1 inactivation decreased the proliferation and increased the migration capacity of contractile SMCs. Detailed characterization of the influence of LRP1 on extracellular matrix maintenance and cellular contraction is ongoing. Conclusions: We confirmed rs11172113 to regulate LRP1 expression in iPSCs derived contractile SMCs. Our results support LRP1 influence on SMCs phenotype as a causal factor in the genetic susceptibility to SCAD and related vascular diseases.

Reversing pathology in a preclinical model of Alzheimer's disease by hacking cerebrovascular neoangiogenesis with advanced cancer therapeutics.

BackgroundCognitive decline leading to dementia, accompanied by the accumulation of amyloid-beta (Aβ) in neuritic plaques together with the appearance of neurofibrillary tangles (NFT) composed of hyperphosphorylated tau protein (tau), are previously noted hallmarks of Alzheimer's disease (AD). We previously discovered hypervascularity in brain specimens from AD patients and consistent with this observation, we demonstrated that overexpression of Aβ drives cerebrovascular neoangiogenesis leading to hypervascularity and coincident tight-junction disruption and blood-brain barrier (BBB) leakiness in animal models of AD. We subsequently demonstrated that amyloid plaque burden and cerebrovascular pathogenesis subside when pro-angiogenic Aβ levels are reduced. Based on these data, we propose a paradigm of AD etiology where, as a compensatory response to impaired cerebral blood flow (CBF), Aβ triggers pathogenic cerebrovascular neoangiogenesis that underlies the conventional hallmarks of AD. Consequently, here we present evidence that repurposing anti-cancer drugs to modulate cerebrovascular neoangiogenesis, rather than directly targeting the amyloid cascade, may provide an effective treatment for AD and related vascular diseases of the brain.MethodsWe explored whether the anti-cancer drug, Axitinib, a small molecule tyrosine kinase inhibitor that targets vascular endothelial growth factor receptors (VEGFR) can inhibit aberrant cerebrovascular neoangiogenic changes, reduce Aβ deposits and reverse cognitive decline in an animal model of AD. One month post-treatment with Axitinib, we employed a battery of tests to assess cognition and memory in aged Tg2576 AD mice and used molecular analysis to demonstrate reduction of amyloid plaques, BBB leakage, hypervascularity and associated disease pathology.FindingsTargeting the pro-angiogenic pathway in AD using the cancer drug, Axitinib, dramatically reduced cerebrovascular neoangiogenesis, restored BBB integrity, resolved tight-junction pathogenesis, diminishes Aβ depositions in plaques and effectively restores memory and cognitive performance in a preclinical mouse model of AD.InterpretationModulation of neoangiogenesis, in an analogous approach to those used to treat aberrant vascularization in cancer and also in the wet form of age-related macular degeneration (AMD), provides an alternative therapeutic strategy for intervention in AD that warrants clinical investigation.

Identification of a new autophagy inhibitor targeting lipid droplets in vascular endothelial cells

Autophagy of vascular endothelial cells (VECs) plays an important role in maintaining vascular homeostasis. Lipid droplets (LDs) are organelles that can be formed in response to various stimuli, including excessive lipid or various stresses. LDs sequester toxic lipids, thereby preventing lipotoxic cell damage and have a complex relationship with autophagy. In the previous study, we identified a novel Grp94 inhibitor HCP1 inhibited apoptosis in VECs. Here we found that HCP1 targeted LDs and promoted the accumulation of LDs in VECs. Our results showed that HCP1 upregulated the protein levels of autophagy-related proteins. We demonstrated that HCP1 upregulated the number of LDs and suppressed autophagy by inhibiting Grp94. Therefore, we provided HCP1 as a new VECs autophagy inhibitor targeting LDs, which might be a potential compound in the treatment of VECs autophagy related vascular diseases.

RNF213 and GUCY1A3 in Moyamoya Disease: Key Regulators of Metabolism, Inflammation, and Vascular Stability.

Moyamoya disease is an idiopathic chronically progressive cerebrovascular disease, which causes both ischemic and hemorrhagic stroke. Genetic studies identified RNF213/Mysterin and GUCY1A3 as disease-causing genes. They were also known to be associated with non-moyamoya intracranial large artery disease, coronary artery disease and pulmonary artery hypertension. This review focused on these two molecules and their strong linker, calcineurin/NFAT signaling and caveolin to understand the pathophysiology of moyamoya disease and related vascular diseases. They are important regulators of lipid metabolism especially lipotoxicity, NF-κB mediated inflammation, and nitric oxide-mediated vascular protection. Although intimal thickening with fibrosis and damaged vascular smooth muscle cells are the distinguishing features of moyamoya disease, origin of the fibrous tissue and the mechanism of smooth muscle cell damages remains not fully elucidated. Endothelial cells and smooth muscle cells have long been a focus of interest, but other vascular components such as immune cells and extracellular matrix also need to be investigated in future studies. Molecular research on moyamoya disease would give us a clue to understand the mechanism preserving vascular stability.

English

Diabetic ulcer is an outcome of the combined effect of diabetes related vascular disease and neuropathy. 1 People prone to diabetes mellitus across the world were estimated to be 131 million in 2000; it is expected to increase to 366 million by 2030. 2 According to several studies, about 25 - 50 % of diabetic patients receive instantaneous amputation at the first visit due to the infection. 3 Slight injury to glucose laden tissue will cause infection which is progressed by an ulcer and it tends to a state of non-healing which has been shown to precede amputation up to 85 % of cases. 4,5 Diabetic ulcer management in the contemporary science includes drainage of pus, debridement of dead tissue, local amputation of necrotic digits and antibiotics.6 Siddha system of medicine also has 64 unique categories of internal and external medicines including 32 in each. 7 Both these ends have their own strengths and limitations too. Though treating a non-healing diabetic ulcer is a very big challenge in the current scenario, an integrated approach will give a light on the path of successful management. P

Cross-Talk of Atherosclerosis and Ischemic Stroke: Dramatic Role of Neutrophils

Context: Current investigations illustrate the increasing prevalence of atherosclerosis (AS) through the aggravating role of inappropriate lifestyle patterns. Atherosclerosis is the cause of important vascular-related diseases such as ischemic stroke (IS). Understanding AS pathophysiology can help reduce the incidence of AS-mediated diseases like ischemic stroke. Evidence Acquisition: For this narrative review article, we used the five mega databases of PubMed, Google Scholar, Scopus, Springer, and Science Direct. We searched from 2010 Jan to 2020 Dec and based on keywords and inclusion criteria, 77 articles were enrolled. Results: Based on prior articles on atherosclerosis and ischemic stroke pathophysiology, local and systemic inflammation is a vigorous factor in both diseasesIndeed, the fundamental inflammatory pathway involved atherosclerosis, and ischemic stroke is associated with the toll-like receptor 4/myeloid differentiation primary response 88/nuclear factor-kappa B (TLR4/ Myd88/ NF-κB) cascade. The functional paw of these intricate mechanisms are pro-inflammatory mediators, such as interleukin-1 beta (IL-1β), tumor necrosis factor (TNF-α), and interleukin-18 (IL-18) incite inflammation. Besides, the essential structures termed inflammasomes (multi proteins components), and multiplicity of immune and non-immune cells (i.e., neutrophils, monocytes, platelets, and macrophages) are beneficial in the induction of inflammatory microenvironment. Conclusions: Neutrophils could be the most effective cells in the inflammation-based mechanism in IS and AS. It is clarified that neutrophils with the recruitment of own vesicles and granules can afford to amplify inflammatory conditions and be a key cell in AS and IS cross-talk. Therefore, utilizing methods to control neutrophils-mediated mechanisms could be an effective method for the prevention of AS and IS.

Jujuboside B Inhibits Neointimal Hyperplasia and Prevents Vascular Smooth Muscle Cell Dedifferentiation, Proliferation, and Migration via Activation of AMPK/PPAR-γ Signaling.

The uncontrolled proliferation and migration of vascular smooth muscle cells is a critical step in the pathological process of restenosis caused by vascular intimal hyperplasia. Jujuboside B (JB) is one of the main biologically active ingredients extracted from the seeds of Zizyphus jujuba (SZJ), which has the properties of anti-platelet aggregation and reducing vascular tension. However, its effects on restenosis after vascular intervention caused by VSMCs proliferation and migration remain still unknown. Herein, we present novel data showing that JB treatment could significantly reduce the neointimal hyperplasia of balloon-damaged blood vessels in Sprague-Dawley (SD) rats. In cultured VSMCs, JB pretreatment significantly reduced cell dedifferentiation, proliferation, and migration induced by platelet-derived growth factor-BB (PDGF-BB). JB attenuated autophagy and reactive oxygen species (ROS) production stimulated by PDGF-BB. Besides, JB promoted the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and the expression of peroxisome proliferator-activated receptor-γ (PPAR-γ). Notably, inhibition of AMPK and PPAR-γ partially reversed the ability of JB to resist the proliferation and migration of VSMCs. Taken as a whole, our findings reveal for the first time the anti-restenosis properties of JB in vivo and in vitro after the endovascular intervention. JB antagonizes PDGF-BB-induced phenotypic switch, proliferation, and migration of vascular smooth muscle cells partly through AMPK/PPAR-γ pathway. These results indicate that JB might be a promising clinical candidate drug against in-stent restenosis, which provides a reference for further research on the prevention and treatment of vascular-related diseases.

Versatile Vessel-on-a-Chip Platform for Studying Key Features of Blood Vascular Tumors

Tumor vessel-on-a-chip systems have attracted the interest of the cancer research community due to their ability to accurately recapitulate the multiple dynamic events of the metastatic cascade. Vessel-on-a-chip microfluidic platforms have been less utilized for investigating the distinctive features and functional heterogeneities of tumor-derived vascular networks. In particular, vascular tumors are characterized by the massive formation of thrombi and severe bleeding, a rare and life-threatening situation for which there are yet no clear therapeutic guidelines. This is mainly due to the lack of technological platforms capable of reproducing these characteristic traits of the pathology in a simple and well-controlled manner. Herein, we report the fabrication of a versatile tumor vessel-on-a-chip platform to reproduce, investigate, and characterize the massive formation of thrombi and hemorrhage on-chip in a fast and easy manner. Despite its simplicity, this method offers multiple advantages to recapitulate the pathophysiological events of vascular tumors, and therefore, may find useful applications in the field of vascular-related diseases, while at the same time being an alternative to more complex approaches.

Vessel segmentation from volumetric images: a multi-scale double-pathway network with class-balanced loss at the voxel level.

Vessel segmentation from volumetric medical images is becoming an essential pre-step in aiding the diagnosis, guiding the therapy, and patient management for vascular-related diseases. Deep learning-based methods have drawn many attentions, but most of them did not fully utilize the multi-scale spatial information of vessels. To address this shortcoming, we propose a multi-scale network similar to the well-known multi-scale DeepMedic. It also includes a double-pathway architecture and a class-balanced loss at the voxel level (MDNet-Vb) to achieve both the computation efficiency and segmentation accuracy. The proposed network consists two parallel pathways to learn the multi-scale vessel morphology. Specifically, the pathway with a normal resolution uses three-dimensional (3D) U-Net fed with small inputs to learn the local details with relatively small storage and time consumption. The pathway with a low-resolution employs 3D fully convolutional network (FCN) fed with downsampled large inputs to learn the overall spatial relationships between vessels and adjacent tissues, and the morphological information of large vessels. To cope with the class-imbalanced issue in vessel segmentation, we propose a class-balanced loss at the voxel level with uniform sampling strategy. The class-balanced loss at the voxel level re-balances the loss function with a coefficient that is inversely proportional to the normalized effective number at the voxel level of each class. The uniform sampling strategy extracts training data by sampling uniformly from two classes in every epoch. Our MDNet-Vb outperforms several state-of-the-art methods including ResNet, DenseNet, 3D U-Net, V-Net, and DeepMedic with the highest dice coefficients of 72.91% and 69.32% on cardiac computed tomography angiography (CTA) dataset and cerebral magnetic resonance angiography (MRA) dataset, respectively. Among four different double-pathway networks, our network (3D U-Net+3D FCN) not only has the fewest training parameters and shortest training time, but also gets competitive dice coefficients on both the CTA and MRA datasets. Compared with classical losses, our class-balanced focal loss (FL-Vb) and dice coefficient loss at the voxel level (Dsc-Vb) alleviates class imbalanced issue by improving both the sensitivity and dice coefficient on the CTA and MRA datasets. Moreover, simultaneously training on two datasets shows that our method has the highest dice coefficient of 73.06% and 65.40% on CTA and MRA datasets, respectively, outperforming the commonly used methods, such as U-Net and DeepMedic, which demonstrates the generalization potential of our network for segmenting different blood vessels. Our MDNet-Vb method demonstrates its superiority over other state-of-the-art methods, on both cardiac CTA and cerebral MRA datasets. For the network architecture, the MDNet-Vb combined the 3D U-Net and 3D FCN, which dramatically reduces the network parameters yet maintains the segmentation accuracy. The class-balanced loss at the voxel level further improves accuracy by properly alleviating the class-imbalanced issue between different classes. In summary, MDNet-Vb is promising for vessel segmentation from various volumetric medical images.

Additive manufacturing of a 3D vascular chip based on cytocompatible hydrogel

Development of a three-dimensional (3D) vascular microfluidic chip is one of the important challenges for the study vascular-related diseases and new drugs. To date, however, realization of in vivo-like blood vessel chips based on soft- or photo-lithographic fabrication methods have limitations such as complex fabrication processes, tedious manual labor, and frequent assembly failure. In this study, we describe the development of a 3D cell culture chip by utilizing a stereolithographic printer. The microfluidic chip was fabricated using a resin made of 30% (v/v in water) poly(ethylene glycol) diacrylate (MW = 700) (30% PEG-DA-700), a UV initiator (Irgacure-819 (IRG)) and a photosensitizer (2-isopropylthioxanthone (ITX)) for constructing a cytocompatible hydrogel structure. The 3D-printed cell culture chip is transparent, enabling cell culture and observation of cell proliferation. Endothelial cells were cultured to mimic in vivo-like blood vessel architecture within the 3D-printed chip. After EAhy926 cell cultivation, cell viability was confirmed by a live/dead cell assay and cultured cells were stained with Calcein-AM (Green) and Ethidium homodim-1 (Red). In addition, endothelial cells were successfully cultured in a 3D-printed vascular tube-like architecture in PEG-DA-700. Creating a vascular microfluidic chip with 30% PEG-DA-700 hydrogel using automated 3D-printing processes reduces fabrication steps and time, avoids any assembly and bonding, and economizes manufacturing cost. We believe our stereolithographic 3D-printing method for fabricating a 3D-printed vascular chip provides a cost-effective, convenient, simple, and reproducible route to vascular-related disease modelling and drug screening analyses.

Early and noninvasive screening of common cardio vascular related diseases such as diabetes and cerebral infarction using photoplethysmograph signals

It is significant to detect the inability of the heart at its early stage, because most of the deaths in all over the world is due to cardiovascular diseases (CVD) (Atlas of Diabetes, 2012). This paper presents a novel learning technique; utilizing Kmeans clustering strategy, Fine Gaussian Multi class Support Vector Machine (FGMSVM) with one-against-one and maximum votingtechnique, to classify the samples to its respective classes, for noninvasive screening of common CVD related diseases. These diseases are investigated by the measurement of Photoplethysmogram (PPG) signals acquired from the subjects with various kinds of diseases. It is seen that the parameters used in this work show clear changes in their values, thus exhibiting their adequacy in recognizing distinctive heart related diseases. The support vectors, which are critical for classification, are obtained by learning from the training samples. Capability of different kernel functions in classification is also demonstrated.

Functional analysis of food components to prevent vascular-related diseases

A Japan-based team of researchers is looking into the disease prevention potential of certain foods, with a focus on the Sakurajima radish, and how it could have a beneficial impact on heart health, specifically cardiovascular health. Given that vascular diseases are the leading cause of death worldwide, the importance of this work cannot be underestimated. At the Faculty of Agriculture, Department of Food Sciences and Biotechnology, Kagoshima University, Japan, Dr. Katsuko Kajiya and her team are researching the bioregulatory functions of agricultural products and how they can be beneficial to health. The researchers are working to scientifically elucidate the function of foods, looking at the disease prevention mechanisms and physiological functions of certain food ingredients.

Autologous correction in patient induced pluripotent stem cell-endothelial cells to identify a novel pathogenic mutation of hereditary hemorrhagic telangiectasia.

Hereditary hemorrhagic telangiectasia is a rare disease with autosomal dominant inheritance. More than 80% hereditary hemorrhagic telangiectasia patients carry heterozygous mutations of Endoglin or Activin receptor-like kinase-1 genes. Endoglin plays important roles in vasculogenesis and human vascular disease. In this report, we found a novel missense mutation (c.88T > C) of Endoglin gene in a hereditary hemorrhagic telangiectasia 1 patient. Induced pluripotent stem cells of the patient were generated and differentiated into endothelial cells. The hereditary hemorrhagic telangiectasia-induced pluripotent stem cells have reduced differentiation potential toward vascular endothelial cells and defective angiogenesis with impaired tube formation. Endoplasmic reticulum retention of the mutant Endoglin (Cys30Arg, C30R) causes less functional protein trafficking to cell surface, which contributes to the pathogenesis of hereditary hemorrhagic telangiectasia. Clustered Regularly Interspaced Short Palindromic Repeats/Cas9 genetic correction of the c.88T > C mutation in induced pluripotent stem cells revealed that C30R mutation of Endoglin affects bone morphogenetic protein 9 downstream signaling. By establishing a human induced pluripotent stem cell from hereditary hemorrhagic telangiectasia patient peripheral blood mononuclear cells and autologous correction on mutant hereditary hemorrhagic telangiectasia-induced pluripotent stem cells, we were able to identify a new disease-causing mutation, which facilitates us to understand the roles of Endoglin in vascular development and pathogenesis of related vascular diseases.

The Glycocalyx and Its Role in Vascular Physiology and Vascular Related Diseases.

PurposeIn 2007 the two senior authors wrote a review on the structure and function of the endothelial glycocalyx layer (Weinbaum in Annu Rev Biomed Eng 9:121–167, 2007). Since then there has been an explosion of interest in this hydrated gel-like structure that coats the luminal surface of endothelial cells that line our vasculature due to its important functions in (A) basic vascular physiology and (B) vascular related diseases. This review will highlight the major advances that have occurred since our 2007 paper.MethodsA literature search mainly focusing on the role of the glycocalyx in the two major areas described above was performed using electronic databases.ResultsIn part (A) of this review, the new formulation of the century old Starling principle, now referred to as the Michel–Weinbaum glycoclayx model or revised Starling hypothesis, is described including new subtleties and physiological ramifications. New insights into mechanotransduction and release of nitric oxide due to fluid shear stress sensed by the glycocalyx are elaborated. Major advances in understanding the organization and function of glycocalyx components, and new techniques for measuring both its thickness and spatio-chemical organization based on super resolution, stochastic optical reconstruction microscopy (STORM) are presented. As discussed in part (B) of this review, it is now recognized that artery wall stiffness associated with hypertension and aging induces glycocalyx degradation, endothelial dysfunction and vascular disease. In addition to atherosclerosis and cardiovascular diseases, the glycocalyx plays an important role in lifestyle related diseases (e.g., diabetes) and cancer. Infectious diseases including sepsis, Dengue, Zika and Corona viruses, and malaria also involve the glycocalyx. Because of increasing recognition of the role of the glycocalyx in a wide range of diseases, there has been a vigorous search for methods to protect the glycocalyx from degradation or to enhance its synthesis in disease environments.ConclusionAs we have seen in this review, many important developments in our basic understanding of GCX structure, function and role in diseases have been described since the 2007 paper. The future is wide open for continued GCX research.

CircAFF1 Aggravates Vascular Endothelial Cell Dysfunction Mediated by miR-516b/SAV1/YAP1 Axis.

Pathological vascular endothelial damage caused by hypoxia is the basis of many vascular-related diseases. However, the role of circular RNA in hypoxic vascular injury is still poorly understood. Here, we found that hypoxia induced AFF1 circular RNA (circAFF1) can activate the SAV1/YAP1 and lead to the dysfunction of vascular endothelial cells. In HUV-EC-C and HBEC-5i cells, circAFF1 was upregulated under CoCl2 induced hypoxic conditions. The abnormal expression of circAFF1 inhibited the proliferation, tube formation, migration of vascular endothelial cells. The effect of circAFF1 is achieved by the adsorption of miR-516b to release SAV1, which in turn causes the phosphorylation of YAP1. Moreover, we found that the upregulation of circAFF1 in 235 Patients with subarachnoid hemorrhage. Taken together, we clarify the role of circAFF1/miR-516b/SAV1/YAP1 axis in vascular endothelial dysfunction and its potential early diagnostic value of disease caused by hypoxia injury in blood vessels.