Pathogenesis Of Vascular Disease Research Articles

N-Acetylcysteine protects against cobalt chloride-induced endothelial dysfunction by enhancing glucose-6-phosphate dehydrogenase activity.

Hypoxia‐induced endothelial dysfunction is known to be involved in the pathogenesis of several vascular diseases. However, it remains unclear whether the pentose phosphate pathway (PPP) is involved in regulating the response of endothelial cells to hypoxia. Here, we established an in vitro model by treating EA.hy926 (a hybrid human umbilical vein cell line) with cobalt chloride (CoCl2; a chemical mimic that stabilizes HIF‐1α, thereby leading to the development of hypoxia), and used this to investigate the involvement of PPP by examining expression of its key enzyme, glucose‐6‐phosphate dehydrogenase (G6PD). We report that CoCl2 induces the accumulation of HIF‐1α, leading to endothelial cell dysfunction characterized by reduced cell viability, proliferation, tube formation, and activation of cytokine production, accompanied with a significant decrease in G6PD expression and activity. The addition of 6‐aminonicotinamide (6‐AN) to inhibit PPP directly causes endothelial dysfunction. Additionally, N‐Acetylcysteine (NAC), a precursor of glutathione, was further evaluated for its protective effects; NAC displayed a protective effect against CoCl2‐induced cell damage by enhancing G6PD activity, and this was abrogated by 6‐AN. The effects of CoCl2 and the involvement of G6PD in endothelial dysfunction have been confirmed in primary human aortic endothelial cells. In summary, G6PD was identified as a novel target of CoCl2‐induced damage, which highlighted the involvement of PPP in regulating the response of endothelial cell CoCl2. Treatment with NAC may be a potential strategy to treat hypoxia or ischemia, which are widely observed in vascular diseases.

CircPCNX Promotes PDGF-BB-Induced Proliferation and Migration of Human Aortic Vascular Smooth Muscle Cells Through Regulating miR-1278/DNMT1 Axis.

Human aortic vascular smooth muscle cells (HA-VSMCs) play vital roles in the pathogenesis of vascular diseases. Circular RNAs (circRNAs) have been reported to regulate the biological functions of HA-VSMCs. In this study, the functions of circRNA pecanex homolog (circPCNX) in platelet-derived growth factor-BB (PDGF-BB)-induced HA-VSMCs were investigated. Quantitative real-time polymerase chain reaction (qRT-PCR) was conducted to determine the expression of circPCNX, DNA methyltransferase 1 (DNMT1), and microRNA-1278 (miR-1278). 5'-Ethynyl-2'-deoxyuridine (EdU) assay, flow cytometry analysis, wound healing assay, and transwell assay were used to examine cell proliferation, cell cycle, and migration. Western blot assay was utilized to measure protein levels. RNA immunoprecipitation (RIP) assay, RNA pull down assay, and dual-luciferase reporter assay were adopted to analyze the relationships among circPCNX, miR-1278, and DNMT1. CircPCNX was upregulated in PDGF-BB-treated HA-VSMCs in a dose- or time-dependent manner. CircPCNX knockdown alleviated PDGF-BB-induced cell proliferation, cell cycle progression, and migration in HA-VSMCs. CircPCNX knockdown could reverse PDGF-BB-induced HA-VSMC progression by regulating DNMT1. Moreover, circPCNX was identified to regulate DNMT1 expression by sponging miR-1278. Inhibition of miR-1278 reversed circPCNX knockdown-mediated effects on cell proliferation and migration in PDGF-BB-induced HA-VSMCs. MiR-1278 overexpression suppressed PDGF-BB-stimulated HA-VSMC proliferation and migration by targeting DNMT1. CircPCNX promoted PDGF-BB-induced HA-VSMC proliferation and migration by elevating DNMT1 expression through sponging miR-1278.

The Effect of Trehalose Supplementation on Macrovascular Inflammation Biomarker in Old Rats by Assessing NFκB-p65 Expression

Background: Vascular inflammation is one of contributing factors to the pathogenesis of arterial aging. Age-related activation of the inflammatory process can lead to various macro-and microvascular pathologies. The pro-inflammatory microenvironment generated in the vascular wall can lead to the pathogenesis of vascular diseases due to an increase in vascular dysfunction. Trehalose is a disaccharide that has several functions, protecting against stressors (one of them is reactive oxygen species/ROS) and preventing the inflammatory responses induced by endotoxic shock. Objectives: To analyze the effect of trehalose supplementation on macrovascular inflammatory processes related to the aging process. Methods: The experimental study used 28 male Wistar rats (Rattus novergicus) which were divided into 4 groups, young control group (Group A), old control group (Group B), 2% sucrose group (Group C), and 2% trehalose group (Group D); were then observed for 8 weeks. Results: The results showed that there were no significant differences in aortic tissue NFκB-p65 expression between old and young subjects (p=0.247). The 2% trehalose group had 40% lower aortic tissue NFkB-p65 expression compared to the old control group (p=0.012); while the group given 2% sucrose solution had a 30% higher aortic tissue NFkB-p65 expression compared to the trehalose group (p=0.018). Conclusion: Trehalose has a good effect on aging-associated vascular inflammatory processes that can be seen from the low aortic tissue NFκB-p65 expression in old rats.

Proteomics of restenosis model in LDLR-deficient hamsters coupled with the proliferative rat vascular smooth muscle cells reveals a new mechanism of vascular remodeling diseases

A major pathological mechanism involved in vascular remodeling diseases is the proliferation and migration of vascular smooth muscle cells. The lipid distribution of golden hamsters is similar to that of humans, which makes them an excellent study model for studying the pathogenesis and molecular characteristics of vascular remodeling diseases. We performed proteomic analysis on Sprague Dawley rat VSMCs (rVSMCs) and restenosis hamsters with low-density lipoprotein receptor (LDLR) deficiency as part of this study. We have also performed the enrichment analysis of differentially modified proteins in regards to Gene Ontology, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, and protein domain. 1070 differentially abundant proteins were assessed in rVSMCs before and after platelet-derived growth factor-BB (PDGF-BB) stimulation. Specifically, 1246 proteins displayed significant differences in the restenosis model in LDLR-deficient hamsters. An analysis of crosstalk between LDLR+/− hamsters artery restenosis and proliferating rVSMCs revealed 130 differentially expressed proteins, including 67 up-regulated proteins and 63 downregulated proteins. Enrichment analysis with KEGG showed differential proteins to be mainly concentrated in metabolic pathways. There are numerous differentially abundant proteins but particularly two proteins (phosphofructokinase 1 of liver type and lactate dehydrogenase A) were found to be up-regulated by PDGF-BB stimulation of rVSMCs and in a restenosis model of hamsters with LDLR+/− expression. SignificanceBased on bioinformatics, we have found glycolysis pathway plays an important role in both the LDLR+/− hamsters restenosis model and the proliferation of rVSMCs. Some key glycolysis enzymes may likely be developed either as new biomarkers or drug targets for vascular remodeling diseases.

Mediterranean G6PD variant rats are protected from Angiotensin II-induced hypertension and kidney damage, but not from inflammation and arterial stiffness

RationaleEpidemiological studies suggest that individuals in the Mediterranean region with deficiency of glucose-6-phosphate dehydrogenase (G6PD) are less susceptible to cardiovascular diseases. However, our knowledge regarding the effects of G6PD deficiency on pathogenesis of vascular diseases caused by factors, like angiotensin II (Ang-II), which stimulate synthesis of inflammatory cytokines and vascular inflammation, is lacking. Furthermore, to-date the effect of G6PD deficiency on vascular health has been controversial and difficult to experimentally prove due to a lack of good animal model. ObjectiveTo determine the effect of Ang-II-induced hypertension (HTN) and stiffness in a rat model of the Mediterranean G6PD (G6PDS188F) variant and in wild-type (WT) rats. Methods and resultsOur findings revealed that infusion of Ang-II (490 ng/kg/min) elicited less HTN and medial hypertrophy of carotid artery in G6PDS188F than in WT rats. Additionally, Ang-II induced less glomerular and tubular damage in the kidneys – a consequence of elevated pressure – in G6PDS188F than WT rats. However, Ang-II-induced arterial stiffness increased in G6PDS188F and WT rats, and there were no differences between the groups. Mechanistically, we found aorta of G6PDS188F as compared to WT rats produced less sustained contraction and less inositol-1,2,3-phosphate (IP3) and superoxide in response to Ang-II. Furthermore, aorta of G6PDS188F as compared to WT rats expressed lower levels of phosphorylated extracellular-signal regulated kinase (ERK). Interestingly, the aorta of G6PDS188F as compared to WT rats infused with Ang-II transcribed more (50-fold) myosin heavy chain-11 (MYH11) gene, which encodes contractile protein of smooth muscle cell (SMC), and less (2.3-fold) actin-binding Rho-activating gene, which encodes a protein that enhances SMC proliferation. A corresponding increase in MYH11 and Leiomodin-1 (LMOD1) staining was observed in arteries of Ang-II treated G6PDS188F rats. However, G6PD deficiency did not affect the accumulation of CD45+ cells and transcription of genes encoding interleukin-6 and collagen-1a1 by Ang-II. ConclusionsThe G6PDS188F loss-of-function variant found in humans protected rats from Ang-II-induced HTN and kidney damage, but not from vascular inflammation and arterial stiffness.

Redox Mechanisms of Platelet Activation in Aging.

Aging is intrinsically linked with physiologic decline and is a major risk factor for a broad range of diseases. The deleterious effects of advancing age on the vascular system are evidenced by the high incidence and prevalence of cardiovascular disease in the elderly. Reactive oxygen species are critical mediators of normal vascular physiology and have been shown to gradually increase in the vasculature with age. There is a growing appreciation for the complexity of oxidant and antioxidant systems at the cellular and molecular levels, and accumulating evidence indicates a causal association between oxidative stress and age-related vascular disease. Herein, we review the current understanding of mechanistic links between oxidative stress and thrombotic vascular disease and the changes that occur with aging. While several vascular cells are key contributors, we focus on oxidative changes that occur in platelets and their mediation in disease progression. Additionally, we discuss the impact of comorbid conditions (i.e., diabetes, atherosclerosis, obesity, cancer, etc.) that have been associated with platelet redox dysregulation and vascular disease pathogenesis. As we continue to unravel the fundamental redox mechanisms of the vascular system, we will be able to develop more targeted therapeutic strategies for the prevention and management of age-associated vascular disease.

Sortilin/Omentin-1 ratio in peripheral artery disease: A cross-sectional study on 295 unselected elderly patients

BackgroundThe role of sortilin and omentin-1 in the pathogenesis of atherosclerosis and vascular disease is an emerging topic in recent years. These molecules can be found circulating in the blood. Recent studies have shown how these biomarkers appear to correlate with the severity of PAD. The levels of these molecules appear to be inversely proportional to each other. Their relationship may provide further insight into the management of the very old diabetic patients with PAD. This study aimed to assess the possible role of sortilin/omentin-1 ratio as easy-to-measure marker in peripheral artery disease (PAD) in type-2 diabetic patients. MethodsThis study analyzed the association between sortilin and omentin-1 serum levels and the presence of clinically significant lower limb PAD in diabetic individuals. We enrolled 295 diabetic patients, including 179 with PAD. Serum levels were collected and correlated with clinical characteristics of the patients. ResultsSortilin concentration was significantly higher in the latter group compared to the former and there was a trend toward increased sortilin levels as disease severity increased. Omentin-1 serum levels were significantly lower in diabetic patients with PAD than in diabetic controls and the levels gradually decreased in proportion to disease severity. The ratio of sortilin to omentin-1 was significantly higher in patients with PAD compared to the other group. ConclusionThe sortilin to omentin-1 ratio appears to be a predictive factor for PAD in patients with type-2 diabetes and it may be a promising marker for clinically significant atherosclerosis of the lower limbs. Further studies are needed to confirm this finding and to evaluate its clinical usefulness.

Hemin-Induced Endothelial Dysfunction and Endothelial to Mesenchymal Transition in the Pathogenesis of Pulmonary Hypertension Due to Chronic Hemolysis.

Pulmonary hypertension in sickle cell disease is an independent predictor of mortality, yet the pathogenesis of pulmonary vascular disease in chronic hemolytic disorders remains incompletely understood and treatment options are limited primarily to supportive care. The release of extracellular hemoglobin has been implicated in the development of pulmonary hypertension, and in this study we explored the direct effects of hemin, the oxidized moiety of heme, on the pulmonary artery endothelium. We found that low dose hemin exposure leads to significantly increased endothelial cell proliferation, migration, and cytokine release as markers of endothelial dysfunction. Protein expression changes in our pulmonary artery endothelial cells showed upregulation of mesenchymal markers after hemin treatment in conjunction with a decrease in endothelial markers. Endothelial to mesenchymal transition (EndoMT) resulting from hemin exposure was further confirmed by showing upregulation of the transcription factors SNAI1 and SLUG, known to regulate EndoMT. Lastly, given the endothelial dysfunction and phenotypic transition observed, the endothelial cytoskeleton was considered a potential novel target. Inhibiting myosin light chain kinase, to prevent phosphorylation of myosin light chain and cytoskeletal contraction, attenuated hemin-induced endothelial hyper-proliferation, migration, and cytokine release. The findings in this study implicate hemin as a key inducer of endothelial dysfunction through EndoMT, which may play an important role in pulmonary vascular remodeling during the development of pulmonary hypertension in chronic hemolytic states.

Fatty Acid-Binding Proteins 4 and 5 Are Involved in the Pathogenesis of Retinal Vascular Diseases in Different Manners.

This study reports on the pathological significance of the vitreous fatty acid-binding protein (Vt-FABP) 4 and 5, and vascular endothelial growth factor A (Vt-VEGFA) in patients with retinal vascular diseases (RVDs) including proliferative diabetic retinopathy (PDR) and retinal vein occlusion (RVO). Subjects with PDR (n = 20), RVO (n = 10), and controls (epiretinal membrane, n = 18) who had undergone vitrectomies were enrolled in this study. The levels of Vt-FABP4, Vt-FABP5, and Vt-VEGFA were evaluated by enzyme-linked immunosorbent assays (ELISA). Retinal circulation levels were measured by a laser-speckle flow analyzer (LSFA) and other relevant data were collected. The Vt-FABP5 levels were significantly (p < 0.05) elevated in patients with RVDs compared to control patients. This elevation was more evident in patients with RVO than with PDR. Log Vt-FABP5 was significantly correlated negatively or positively with all the LSFA retinal circulation indexes or Log triglycerides (r = 0.31, p = 0.031), respectively. However, the elevations in the Vt-FABP4 and Vt-VEGFA levels were more evident in the PDR group (p < 0.05) and these factors were correlated positively with Log fasting glucose and negatively with some of the LSFA retinal circulation indexes. Multivariable regression analyses indicated that the LSFA blood flows of the optic disc at baseline was an independent effector with Log Vt-FABP5 other than several possible factors including age, gender, Log triglycerides, Log Vt-FABP4 and Log Vt-VEGFA. These current findings suggest that Vt-FABP5 is involved in the pathogenesis of RVD in a manner that is different from that for Vt-FABP4 and Vt-VEGFA, presumably by regulating retinal circulation.

Sortilin, carbamylation, and cardiovascular calcification in chronic kidney disease

Sortilin appears to play important roles in the pathogenesis of vascular and metabolic diseases, such as cardiovascular calcification. Post-translational modifications of sortilin (i.e., phosphorylation or carbamylation) are among the key mechanisms of its actions. Recent data extended the role of carbamylated sortilin to the pathogenesis of cardiovascular calcifications in chronic kidney disease. Whether therapeutic tools potentially available to inhibit the carbamylation process in chronic kidney disease patients would allow preventing cardiovascular calcifications remains to be demonstrated.

Exploring the Relationship of Perivascular Adipose Tissue Inflammation and the Development of Vascular Pathologies.

Initially thought to only provide mechanical support for the underlying blood vessels, perivascular adipose tissue (PVAT) has now emerged as a regulator of vascular function. A healthy PVAT exerts anticontractile and anti-inflammatory actions on the underlying vasculature via the release of adipocytokines such as adiponectin, nitric oxide, and omentin. However, dysfunctional PVAT produces more proinflammatory adipocytokines such as leptin, resistin, interleukin- (IL-) 6, IL-1β, and tumor necrosis factor-alpha, thus inducing an inflammatory response that contributes to the pathogenesis of vascular diseases. In this review, current knowledge on the role of PVAT inflammation in the development of vascular pathologies such as atherosclerosis and hypertension was discussed.

Neuroinflammation and Neuropathology.

This review addresses the current understanding of the role of autoimmune neuroinflammation in the pathogenesis of vascular, neurodegenerative, and other diseases of the nervous system. The mechanisms of responses of resident CNS cells (glial cells, astrocytes) and peripheral immune system cells are presented. The therapeutic potentials of phosphodiesterase inhibitors, which have antiaggregant properties and can suppress autoimmune inflammation, are discussed. The phosphodiesterase inhibitor dipyridamole is regarded as a potential drug for this purpose.

Abstract TMP116: Pharmacological Inhibition Of Endoplasmic Reticulum Stress Prevents Intracranial Aneurysm Rupture

Background: The endoplasmic reticulum (ER) is responsible for cellular protein synthesis and folding. Cellular stimuli that perturb ER homeostasis create an imbalance between the protein-folding load and capacity of ER, causing unfolded or misfolded proteins to accumulate in the ER lumen, known as ER stress. Recent studies suggested that ER stress plays significant roles in the pathogenesis of inflammatory vascular diseases. Since inflammation is emerging as a vital component of the pathophysiology of intracranial aneurysms, we hypothesized that ER stress promotes the development of aneurysm rupture by inducing sustained vascular wall inflammation. We tested this hypothesis utilizing pharmacological approaches in mice. Methods: We used 10-week-old male C57BL/6J mice and induced intracranial aneurysms by combining an elastase injection and hypertension. We tested the effects of an ER stress activator (Tunicamycin) and inhibitor (4-phenylbutyric acid, 4-PBA) on the development of aneurysmal rupture. In addition, we assessed the roles of ER stress induced via deactivation of epidermal growth factor receptor (EGFR) by Erlotinib on aneurysm rupture. Results: The pharmacological inhibition of ER stress significantly decreased the rupture rate (P&lt;0.05, Fig. A). Meanwhile, there was a trend for the ER stress activator to increase the rupture rate (P=0.17, Fig.B). Moreover, the pharmacological inhibition of the EGFR pathway with Erlotinib significantly reduced the rupture rate (P&lt;0.05, Fig. C). In addition, Erlotinib treatment reduced the mRNA expression of ER stress markers GRP78 and CHOP (Fig.D-E). Conclusions: The pharmacological inhibition of ER stress decreased aneurysmal rupture in a mouse model of intracranial aneurysm. In addition, inhibition of EGFR decreased aneurysm rupture through the reduction of ER stress. Our findings suggest that ER stress and its upstream EGFR pathway may serve as novel therapeutic targets for preventing aneurysm rupture.

Hemodynamic Forces, Endothelial Mechanotransduction, and Vascular Diseases.

Cells in the tissues and organs of a living body are subjected to mechanical forces, such as pressure, friction, and tension from their surrounding environment. Cells are equipped with a mechanotransduction mechanism by which they perceive mechanical forces and transmit information into the cell interior, thereby causing physiological or pathogenetic mechano-responses. Endothelial cells (ECs) lining the inner surface of blood vessels are constantly exposed to shear stress caused by blood flow and a cyclic strain caused by intravascular pressure. A number of studies have shown that ECs are sensitive to changes in these hemodynamic forces and alter their morphology and function, sometimes by modifying gene expression. The mechanism of endothelial mechanotransduction has been elucidated, and the plasma membrane has recently been shown to act as a mechanosensor. The lipid order and cholesterol content of plasma membranes change immediately upon the exposure of ECs to hemodynamic forces, resulting in a change in membrane fluidity. These changes in a plasma membrane's physical properties affect the conformation and function of various ion channels, receptors, and microdomains (such as caveolae and primary cilia), thereby activating a wide variety of downstream signaling pathways. Such endothelial mechanotransduction works to maintain circulatory homeostasis; however, errors in endothelial mechanotransduction can cause abnormalities in vascular physiological function, leading to the initiation and progression of various vascular diseases, such as hypertension, thrombosis, aneurysms, and atherosclerosis. Recent advances in detailed imaging technology and computational fluid dynamics analysis have enabled us to evaluate the hemodynamic forces acting on vascular tissue accurately, contributing greatly to our understanding of vascular mechanotransduction and the pathogenesis of vascular diseases, as well as the development of new therapies for vascular diseases.

Circular RNA circEsyt2 regulates vascular smooth muscle cell remodeling via splicing regulation.

Circular RNAs (circRNAs) have been recently recognized as playing a role in the pathogenesis of vascular remodeling-related diseases by modulating the functions of miRNAs. However, the interplay between circRNAs and proteins during vascular remodeling remains poorly understood. Here, we investigated a previously identified circRNA, circEsyt2, whose expression is known to be upregulated during vascular remodeling. Loss- and gain-of‑function mutation analyses in vascular smooth muscle cells (VSMCs) revealed that circEsyt2 enhanced cell proliferation and migration and inhibited apoptosis and differentiation. Furthermore, the silencing of circEsyt2 in vivo reduced neointima formation, while circEsyt2 overexpression enhanced neointimal hyperplasia in the injured carotid artery, confirming its role in vascular remodeling. Using unbiased protein-RNA screening and molecular validation, circEsyt2 was found to directly interact with polyC-binding protein 1 (PCBP1), an RNA splicing factor, and regulate PCBP1 intracellular localization. Additionally, circEsyt2 silencing substantially enhanced p53β splicing via the PCBP1-U2AF65 interaction, leading to the altered expression of p53 target genes (cyclin D1, p21, PUMA, and NOXA) and the decreased proliferation of VSMCs. Thus, we identified a potentially novel circRNA that regulated vascular remodeling, via altered RNA splicing, in atherosclerotic mouse models.

Mitochondrial Dynamics: Pathogenesis and Therapeutic Targets of Vascular Diseases.

Vascular diseases, particularly atherosclerosis, are associated with high morbidity and mortality. Endothelial cell (EC) or vascular smooth muscle cell (VSMC) dysfunction leads to blood vessel abnormalities, which cause a series of vascular diseases. The mitochondria are the core sites of cell energy metabolism and function in blood vessel development and vascular disease pathogenesis. Mitochondrial dynamics, including fusion and fission, affect a variety of physiological or pathological processes. Multiple studies have confirmed the influence of mitochondrial dynamics on vascular diseases. This review discusses the regulatory mechanisms of mitochondrial dynamics, the key proteins that mediate mitochondrial fusion and fission, and their potential effects on ECs and VSMCs. We demonstrated the possibility of mitochondrial dynamics as a potential target for the treatment of vascular diseases.

A Nitric Oxide–Modulated Variable-Order Fractional Maxwell Viscoelastic Model of Cerebral Vascular Walls

It is well known that the mechanical behavior of arterial walls plays an important role in the pathogenesis of vascular diseases. Most studies existing in the literature focus on the mechanical interactions between the blood flow and wall’s deformations. However, in the brain, the smaller vessels experience not only oscillatory forces due to the pulsatile blood flow but also structural and morphological changes controlled by the surrounding brain cells. In this study, the mechanical deformation of the cerebral arterial wall caused by the pulsatile blood flow and the dynamics of the neuronal nitric oxide (NO) is investigated. NO is a small diffusive gaseous molecule produced by the endothelial cells and neurons, which is involved in the regulation of cerebral blood flow and pressure. The cerebral vessel is assumed to be a hollow axial symmetric cylinder whose wall thickness is much smaller than the cylinder’s radius and longitudinal length is much less than the propagating wavelength. The wall is an isotropic, homogeneous linear viscoelastic material described by an NO-modulated variable-order fractional Maxwell model. A fractional telegraph equation is obtained for the axial component of the displacement. Patterns of wall’s deformation are investigated through numerical simulations. The results suggest that a significantly decreased inactivation of the neuronal NO may cause a reduction in the shear stress at the blood-vessel interface, which could lead to a decrease in the production of shear-induced endothelial NO and neurovascular disease.

Molecular and Cellular Dynamics of Aortic Aneurysms Revealed by Single-Cell Transcriptomics.

The aorta is highly heterogeneous, containing many different types of cells that perform sophisticated functions to maintain aortic homeostasis. Recently, single-cell RNA sequencing studies have provided substantial new insight into the heterogeneity of vascular cell types, the comprehensive molecular features of each cell type, and the phenotypic interrelationship between these cell populations. This new information has significantly improved our understanding of aortic biology and aneurysms at the molecular and cellular level. Here, we summarize these findings, with a focus on what single-cell RNA sequencing analysis has revealed about cellular heterogeneity, cellular transitions, communications among cell populations, and critical transcription factors in the vascular wall. We also review the information learned from single-cell RNA sequencing that has contributed to our understanding of the pathogenesis of vascular disease, such as the identification of cell types in which aneurysm-related genes and genetic variants function. Finally, we discuss the challenges and future directions of single-cell RNA sequencing applications in studies of aortic biology and diseases.

Diagnostic and Prognostic Value of Immune/Inflammation Biomarkers for Venous Thromboembolism: Is It Reliable for Clinical Practice?

Venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE), has been an important cause of sudden in-hospital death. Studies have shown that the immune/inflammatory response plays an important role in the pathogenesis of vascular disease, with representative markers in the blood including the neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), monocyte/lymphocyte ratio (MLR), systemic immune/inflammatory index (SII), etc. However, there is a variety of immune/inflammatory indicators. Moreover, most previous studies have been single-center investigations involving one or two indicators, with varying nature of cases, number of cases and study objectives, thereby making it difficult to reach consensus conclusions with good clinical guidelines. This article reviews the clinical value of immunoinflammatory indicators for VTE based on previous studies, including the diagnostic and prognostic capabilities. In conclusion, NLR provides promising predictive capability for the onset and prognosis of VTE and deserves extensive application in clinical practice. PLR also has certain diagnostic and prognostic value, but further studies are warranted to identify its reliability and stability. Monocytes, eosinophils and platelet-related indicators show some clinical association with VTE, although the predictive capabilities are mediocre. SII is of promising potential value for VTE and deserves further investigations. This review will provide new clues and valuable clinical guidance for the diagnosis and therapy of VTE.

Circ_CHFR regulates ox-LDL-mediated cell proliferation, apoptosis, and EndoMT by miR-15a-5p/EGFR axis in human brain microvessel endothelial cells.

Oxidized low-density lipoprotein (ox-LDL) is a significant risk factor for various brain vascular diseases. Circular RNA (circRNA) is involved in the pathogenesis of brain vascular diseases. This study revealed the roles of circ_CHFR in ox-LDL-mediated cell proliferation, apoptosis, and endothelial-to-mesenchymal transition (EndoMT). Our results showed that circ_CHFR and EGFR expressions were dramatically upregulated, while miR-15a-5p expression was downregulated in ox-LDL-induced human brain microvessel endothelial cells (HBMECs) relative to control groups. circ_CHFR knockdown hindered the effects of ox-LDL exposure on cell proliferation, cell cycle, apoptosis, and EndoMT in HBMECs, whereas these impacts were abolished by miR-15a-5p inhibitor. In addition, circ_CHFR functioned as a sponge of miR-15a-5p and miR-15a-5p bound to EGFR. Thus, we concluded that circ_CHFR silencing hindered ox-LDL-mediated cell proliferation, apoptosis, and EndoMT by downregulating EGFR expression through sponging miR-15a-5p in HBMECs. Our findings provide a new mechanism for studying circRNA-directed therapy in ox-LDL-induced human brain vascular diseases.