Development Of Vascular Disease Research Articles

Inflammation: Is It a Healer, Confounder, or a Promoter of Cardiometabolic Risks?

Inflammation is the body’s non-specific response to injury or infection. It is a natural defense mechanism that helps to maintain homeostasis and promotes tissue repair. However, excessive inflammation can lead to cellular, tissue, or organ dysfunction, as well as contribute to the development of acute vascular events and diseases like Crohn’s disease, psoriasis, obesity, diabetes, and cancer. The initial response to injury involves the activation of platelets and coagulation mechanisms to stop bleeding. This is followed by the recruitment of immune cells and the release of cytokines to promote tissue repair. Over time, the injured tissue undergoes remodeling and returns to its pre-injury state. Inflammation is characterized by the activation of inflammatory signaling pathways involving cytokines, chemokines, and growth factors. Mast cells play a role in initiating inflammatory responses. Pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs) and nucleotide-binding domain (NOD)-like receptors (NLRs) are involved in the activation of these inflammatory pathways. Inflammasomes, which are cytoplasmic complexes, also contribute to inflammation by activating cytokines. Inflammation can also be triggered by factors like dietary components and the composition of the gut microbiota. Dysregulation of the gut microbiome can lead to excessive inflammation and contribute to diseases like atherosclerosis and irritable bowel syndrome (IBS). The immune system and gut-associated lymphoid tissue (GALT) play crucial roles in the inflammatory response and the development of conditions like colorectal cancer. Anti-inflammatory therapy can play a significant role in reducing or inducing the remission of inflammatory diseases such as Crohn’s disease and ulcerative colitis. The fetal origin of adult diseases theory suggests that conditions during fetal development, such as low birth weight and maternal obesity, can influence the risk of cardiometabolic diseases later in life. All of the known risk factors associated with cardiometabolic diseases such as hypertension, excess weight, obesity, type-2 diabetes, and vascular diseases are accompanied by chronic low-grade inflammation. Inflammation seems to have a role in precipitating even acute vascular events such as heart attacks and stroke. Common markers of inflammation associated with cardiometabolic disease include interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF-α), C-reactive protein (CRP), and soluble TNF receptors such as sTNFR1 and sTNFR2. These markers serve as indicators of systemic inflammation. However, these markers are not disease-specific but provide an insight into the overall chronic inflammatory status. In fact, inflammation has been identified as a potential target for future treatments to reduce or reverse the risk of atherosclerosis-related complications. The regulation of inflammation is complex, and further research is needed to better understand its mechanisms and develop strategies for managing inflammatory disorders. In summary, inflammation is a natural response to injury or infection, but excessive or prolonged inflammation can lead to the progression of various diseases. Understanding the underlying mechanisms of inflammation is important for developing treatments and preventive measures for inflammatory disorders.

High prevalence of short telomeres in idiopathic porto-sinusoidal vascular disorder.

Telomeres prevent damage to coding DNA as end-nucleotides are lost during mitosis. Mutations in telomere maintenance genes cause excessive telomere shortening, a condition known as short telomere syndrome (STS). One hepatic manifestation documented in STS is porto-sinusoidal vascular disorder (PSVD). As the etiology of many cases of PSVD remains unknown, this study explored the extent to which short telomeres are present in patients with idiopathic PSVD. This monocentric cross-sectional study included patients with histologically defined idiopathic PSVD. Telomere length in 6 peripheral blood leukocyte subpopulations was assessed using fluorescent in situ hybridization and flow cytometry. Variants of telomere-related genes were identified using high-throughput exome sequencing. In total, 22 patients were included, of whom 16 (73%) had short (9/22) or very short (7/22) telomeres according to age-adjusted reference ranges. Fourteen patients (64%) had clinically significant portal hypertension. Shorter telomeres were more frequent in males (p = 0.005) and patients with concomitant interstitial lung disease (p < 0.001), chronic kidney disease (p < 0.001), and erythrocyte macrocytosis (p = 0.007). Portal hypertension (p = 0.021), low serum albumin level (p < 0.001), low platelet count (p = 0.007), and hyperbilirubinemia (p = 0.053) were also associated with shorter telomeres. Variants in known STS-related genes were identified in 4 patients with VSTel and 1 with STel. Short and very short telomeres were highly prevalent in patients with idiopathic PSVD, with 31% presenting with variants in telomere-related genes. Telomere biology may play an important role in vascular liver disease development. Clinicians should consider measuring telomeres in any patient presenting with PSVD.

THE ROLE OF FOLATE, VITAMIN B12 AND B6 IN HYPERHOMOCYSTEINEMIA AS THE RISK FACTOR OF CARDIOVASCULAR DISEASE: NARRATIVE REVIEW

Cardiovascular disease (CVD), encompassing ailments affecting the heart and vascular system, is estimated to contribute to one-third of global mortality, and its prevalence is continuously rising. The etiology of this condition is multifactorial, making it challenging to identify a singular causative factor. Homocysteine, a factor identified in the 1990s, is known to contribute to the development of atherosclerotic vascular disease and hypercoagulability. Although there is a definite connection, the assessment and management of this condition are still a subject of debate due to inconsistent research findings on its impact in lowering the risk of cardiovascular disease. B vitamins are a collection of chemical compounds that play a crucial role in physiological function. However, the body does not produce them naturally and they need to be obtained from dietary intake. Vitamins B6, B9, and B12 are crucial in the metabolism of homocysteine. The cause of hyperhomocysteinemia is believed to be a deficiency of certain vitamins, particularly folate, B12, and B6, which are important for effectively recycling homocysteine in the methionine cycle. Vitamin B is intricately linked to both the homocysteine and cardiovascular disease (CVD) pathways.

Cardiovascular toxicity of chemotherapy and thyroid status of patients with gastric and colon cancer: Current state of the problem. A review

Cardiovascular and oncological diseases are the main causes of disability and mortality in Russia, sharing common risk factors and exacerbating each other. The specific toxicological effects of fluoropyrimidines, platinum drugs, and taxanes commonly used in the treatment of gastric and colorectal malignancies have been noted to potentially contribute to the onset of cardiovascular pathologies in some cases. However, the manifestation and prevalence of cardiovascular toxicity due to cancer treatment regimens are influenced by various factors beyond just the chemotherapy protocols employed. Gender, age, overall health status (including cardiac and thyroid functions), and other risk factors play significant roles in the development and progression of heart and vascular diseases in these patients. Thyroid dysfunction, even in the absence of severe clinical symptoms, can significantly impact the course of cardiovascular pathologies, complicating the management of toxic effects associated with polychemotherapy on both the cardiac muscle and vascular system. This paper analyzes modern ideas about pathogenetic relationship between cardiovascular diseases and gastric and colon cancer. The profile and mechanism of cardiovascular toxicity of chemotherapy in patients with gastric and colon cancer, pathogenetic relationship of thyroid status and cardiovascular diseases are presented. Organizational management issues of chemotherapy toxicity are briefly highlighted.

Evaluation of proprotein convertase subtilsin /kexin 9(PCSK9) in serum of men hypertensive patients

High blood pressure is considered a major factor for the development of heart disease and vascular disease in elderly people, due to higher tension in arteries leading to hypertension. PCSK9 is a proprotein convertase that increases circulating LDL levels by directing hepatic LDL receptors into lysosomes for degradation. The effects of PCSK9 on hepatic LDL receptors and contribution to atherosclerosis via the induction of hyperlipidemia are well defined. Methods: The case-control study included (90) subjects divided into sixty (60) male patients. Samples were collected for patients with high blood pressure in Al-Sadr Medical City in Najaf Al-Ashraf / Iraq, and laboratory tests were conducted to measure the lipid profile in Al-Sadr Medical City laboratories. Height and weight were measured, and other information was also collected. The ELISA test was performed in the advanced animal laboratory in the college’s Department of Biology. Department of Science/University of Kufa. The study was conducted by collecting samples and measuring all factors in the period from 1/11/2023 to 2/2/2024. A control group study of 30 men was also conducted. All groups that appeared healthy were matched in age, and patients with diabetes, kidney disease and heart disease were excluded from the study, as well as any other systemic diseases. Conclusion: The present study concluded that PCSK9considered as a prognostic marker for prediction of hypertension. Also, PCSK9 was very related in hypertensive patients with hyperlipidemia (cholesterol, TG, LDL, &amp; HDL). High biomarker level associated with ages especially at new diagnosis without treatment and with short duration of disease. Smoking plays important roles with high a level of PCSK9 in hypertensive patients. The genetic may play a role in present study by high level of This biomarker in familial hypertensive patients. Obesity has a crucial role in in hypertensive patients with high PCSK9 level.

Non-neuronal cell-derived acetylcholine, a key modulator of the vascular endothelial function in health and disease.

Vascular endothelial cells play an important role in regulating peripheral circulation by modulating arterial tone in the microvasculature. Elevated intracellular Ca2+ levels are required in endothelial cells to induce smooth muscle relaxation via endothelium-dependent mechanisms such as nitric oxide production, prostacyclin, and endothelial cell hyperpolarization. It is well established that exogenous administration of acetylcholine can increase intracellular Ca2+ concentrations, followed by endothelium-dependent vasodilation. Although endogenous acetylcholine's regulation of vascular tone remains debatable, recent studies have reported that endogenously derived acetylcholine, but not neuronal cell-derived acetylcholine, is a key modulator of endothelial cell function. In this minireview, we summarize the current knowledge of the non-neuronal cholinergic system (NNCS) in vascular function, particularly vascular endothelial cell function, which contributes to blood pressure regulation. We also discuss the possible pathophysiological impact of endothelial NNCS, which may induce the development of vascular diseases due to endothelial dysfunction, and the potential of endothelial NNCS as a novel therapeutic target for endothelial dysfunction in the early stages of metabolic syndrome, diabetes, and hypertension.

The Role of Autophagy in Vascular Endothelial Cell Health and Physiology.

Autophagy is a highly conserved cellular recycling process which enables eukaryotes to maintain both cellular and overall homeostasis through the catabolic breakdown of intracellular components or the selective degradation of damaged organelles. In recent years, the importance of autophagy in vascular endothelial cells (ECs) has been increasingly recognized, and numerous studies have linked the dysregulation of autophagy to the development of endothelial dysfunction and vascular disease. Here, we provide an overview of the molecular mechanisms underlying autophagy in ECs and our current understanding of the roles of autophagy in vascular biology and review the implications of dysregulated autophagy for vascular disease. Finally, we summarize the current state of the research on compounds to modulate autophagy in ECs and identify challenges for their translation into clinical use.

Knockout of LRRC8A Anion Channels in Vascular Smooth Muscle Cells Impairs NF-κB and Hif1α-mediated Signaling

Vascular smooth muscle cell (VSMC) inflammation associated with the development of vascular disease, including hypertension. We have demonstrated that knockout (KO) or inhibition of LRRC8A anion channels in VSMCs attenuates reactive oxygen species (ROS) production by NADPH oxidase 1, impairs TNFα-induced inflammation, and promotes vascular relaxation in murine mesenteric arteries. To explore the mechanism of these effects we performed RNA sequencing (RNAseq) on LRRC8A wild-type (WT) and knockout (KO) VSMCs (N = 3 pairs) under control conditions and 6hrs following TNFα treatment (10ng/ml). The data were normalized by Median ratio (DESeq2) and differential expression was determined by DESeq2 method using Partek software and pathway enrichment analysis was done by KEGG pathway. Differential expression of genes of interest was confirmed by quantitative PCR (qPCR) in both cultured cells and in whole aortic tissues (endothelium-denuded, N = 3) from LRRC8A WT and KO mice. HIF1α transcriptional activity was quantified by luciferase reporter assays in cells exposed to hypoxia (1% oxygen) or cobalt chloride (300μM) for 6 hrs. RNAseq demonstrated broad impairment of pro-inflammatory signaling in KO cells. This was consistent with previous observations of impaired nuclear factor kappa B (NF-κB) reporter activation by TNFα in the absence of LRRC8A. Compared to WT VSMCs, resting LRRC8A KO VSMCs exhibited statistically significant downregulation of 33 NF-κB target genes including the IL-6 (Il6) and IL-1β (Il1r1) receptors. TNFα treatment increased the expression of 37 NF-κB target genes in WT cells. Most of these genes (34 genes) were not significantly activated by TNFα in KO cells, while 3 genes (chemokine (C-C motif) ligand 20; CCL20, prostaglandin E synthase; PTGES and vascular endothelial growth factor C; VEGFC) were significantly downregulated. Pathway analysis data revealed that Hif1α signaling appear in the top downregulated pathway and it was impaired as 14 Hif1α target genes were downregulated in unstimulated KO VSMCs. In addition, expression of Rps4i, a long non-coding mRNA associated with inhibition of HIF1α signaling was significantly upregulated. Luciferase reporter assays following exposure to hypoxia or cobalt chloride confirmed impaired Hif1α activation in LRRC8A KO cells. Important target genes for HIF1α, including HK2, LDHB, ACE, BMP4 and PFKP, were less activated, while RPS4i remained upregulated compared to WT cells. These findings demonstrate disruption of both NF-κB and HIF1α signaling in VSMCs lacking LRRC8A. This anion channel represents a novel target for anti-inflammatory therapy in vascular disease. This work was supported by DK132948 and HL160975. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Puerarin mitigated LPS-ATP or HG-primed endothelial cells damage and diabetes-associated cardiovascular disease via ROS-NLRP3 signalling.

The occurrence and development of diabetic vascular diseases are closely linked to inflammation-induced endothelial dysfunction. Puerarin (Pue), the primary component of Pueraria lobata, possesses potent anti-inflammatory properties. However, its vasoprotective role remains elusive. Therefore, we investigated whether Pue can effectively protect against vascular damage induced by diabetes. In the study, Pue ameliorated lipopolysaccharide-adenosine triphosphate (LPS-ATP) or HG-primed cytotoxicity and apoptosis, while inhibited reactive oxygen species (ROS)-mediated NLR family pyrin domain containing 3 (NLRP3) inflammasome in HUVECs, as evidenced by significantly decreased ROS level, NOX4, Caspase-1 activity and expression of NLRP3, GSDMD, cleaved caspase-1, IL-1β and IL-18. Meanwhile, ROS inducer CoCI2 efficiently weakened the effects of Pue against LPS-ATP-primed pyroptosis. In addition, NLRP3 knockdown notably enhanced Pue's ability to suppress pyroptosis in LPS-ATP-primed HUVECs, whereas overexpression of NLRP3 reversed the inhibitory effects of Pue. Furthermore, Pue inhibited the expression of ROS and NLRP3 inflammasome-associated proteins on the aorta in type 2 diabetes mellitus rats. Our findings indicated that Pue might ameliorate LPS-ATP or HG-primed damage in HUVECs by inactivating the ROS-NLRP3 signalling pathway.

Cytosolic DNA initiates a vicious circle of aging-related endothelial inflammation and mitochondrial dysfunction via STING: the inhibitory effect of Cilostazol.

Endothelial senescence, aging-related inflammation, and mitochondrial dysfunction are prominent features of vascular aging and contribute to the development of aging-associated vascular disease. Accumulating evidence indicates that DNA damage occurs in aging vascular cells, especially in endothelial cells (ECs). However, the mechanism of EC senescence has not been completely elucidated, and so far, there is no specific drug in the clinic to treat EC senescence and vascular aging. Here we show that various aging stimuli induce nuclear DNA and mitochondrial damage in ECs, thus facilitating the release of cytoplasmic free DNA (cfDNA), which activates the DNA-sensing adapter protein STING. STING activation led to a senescence-associated secretory phenotype (SASP), thereby releasing pro-aging cytokines and cfDNA to further exacerbate mitochondrial damage and EC senescence, thus forming a vicious circle, all of which can be suppressed by STING knockdown or inhibition. Using next-generation RNA sequencing, we demonstrate that STING activation stimulates, whereas STING inhibition disrupts pathways associated with cell senescence and SASP. In vivo studies unravel that endothelial-specific Sting deficiency alleviates aging-related endothelial inflammation and mitochondrial dysfunction and prevents the development of atherosclerosis in mice. By screening FDA-approved vasoprotective drugs, we identified Cilostazol as a new STING inhibitor that attenuates aging-related endothelial inflammation both in vitro and in vivo. We demonstrated that Cilostazol significantly inhibited STING translocation from the ER to the Golgi apparatus during STING activation by targeting S162 and S243 residues of STING. These results disclose the deleterious effects of a cfDNA-STING-SASP-cfDNA vicious circle on EC senescence and atherogenesis and suggest that the STING pathway is a promising therapeutic target for vascular aging-related diseases. A proposed model illustrates the central role of STING in mediating a vicious circle of cfDNA-STING-SASP-cfDNA to aggravate age-related endothelial inflammation and mitochondrial damage.

Aged-vascular niche hinders osteogenesis of mesenchymal stem cells through paracrine repression of Wnt-axis.

Age-induced decline in osteogenic potential of bone marrow mesenchymal stem cells (BMSCs) potentiates osteoporosis and increases the risk for bone fractures. Despite epidemiology studies reporting concurrent development of vascular and bone diseases in the elderly, the underlying mechanisms for the vascular-bone cross-talk in aging are largely unknown. In this study, we show that accelerated endothelial aging deteriorates bone tissue through paracrine repression of Wnt-driven-axis in BMSCs. Here, we utilize physiologically aged mice in conjunction with our transgenic endothelial progeria mouse model (Hutchinson-Gilford progeria syndrome; HGPS) that displays hallmarks of an aged bone marrow vascular niche. We find bone defects associated with diminished BMSC osteogenic differentiation that implicate the existence of angiocrine factors with long-term inhibitory effects. microRNA-transcriptomics of HGPS patient plasma combined with aged-vascular niche analyses in progeria mice reveal abundant secretion of Wnt-repressive microRNA-31-5p. Moreover, we show that inhibition of microRNA-31-5p as well as selective Wnt-activator CHIR99021 boosts the osteogenic potential of BMSCs through de-repression and activation of the Wnt-signaling, respectively. Our results demonstrate that the vascular niche significantly contributes to osteogenesis defects in aging and pave the ground for microRNA-based therapies of bone loss in elderly.

Mechanical, structural, and morphological differences in the iliac arteries

Iliac arteries play a crucial role in peripheral blood circulation. They are susceptible to various diseases, including aneurysms and atherosclerosis. Structure, material properties, and biomechanical forces acting on different regions of the iliac vasculature may contribute to the localization and progression of these pathologies. We examined 33 arterial specimens from common iliac (CI), external iliac (EI), and internal iliac (II) arteries obtained from 11 human donors (62 ± 12 years). We conducted morphometric, mechanical, and structural analyses using planar biaxial tests, constitutive modeling, and bi-directional histology on transverse and axial sections. The iliac arteries exhibited increased tortuosity and varying disease distribution with age. CI and II arteries displayed non-uniform age-related disease progression around their circumference, while EI remained healthy even in older individuals. Trends in load-free and stress-free thickness varied along the iliac vasculature. Longitudinally, EI exhibited the highest compliance compared to other iliac vessels. In contrast, CI was stiffest longitudinally, and EI was the stiffest circumferentially. Material parameters for all iliac vessels are reported for four common constitutive relations. Elastin near the internal elastic lamina displayed greater waviness in EI and II compared to CI. Also, EI had the least glycosaminoglycans (GAGs) and the highest elastin content. Our findings highlight variations in the morphological, mechanical, and structural properties of iliac arteries along their length. This data can inform vascular disease development and computational studies, and guide the development of biomimetic repair materials and devices tailored to specific iliac locations, improving vascular repair strategies.

Non-Coding RNAs: Novel Regulators of Macrophage Homeostasis in Ocular Vascular Diseases.

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

Vascular Endothelial Growth Factor Inhibitors and the Risk of Aortic Aneurysm and Aortic Dissection

Vascular endothelial growth factor pathway inhibitors (VPIs) pose a concern for aortic aneurysm (AA) and aortic dissection (AD), signaling potential vascular disease development. To investigate VPI-associated AA and AD. This case-control study with a nested design used full population data from a national claims database in Taiwan between 2011 and 2019. Eligible participants were aged 20 years or older with kidney, hepatic, gastrointestinal, or pancreatic cancer diagnosed between January 1, 2012, and December 31, 2019. The first cancer diagnosis date was defined as the cohort entry date. Cases were patients who received a diagnosis of AA or AD in hospitalizations or emergency visits between the cohort entry date and December 31, 2019. Controls were matched by ratio (up to 1:5) based on age, sex, cancer type, cohort entry date, and the index date (ie, the first AA or AD event date). Data analysis was performed between January 2022 and December 2023. Use of the oral VPIs sorafenib, sunitinib, and pazopanib between cohort entry date and index date. In the primary analysis, AA and AD were evaluated compositely, while in the secondary analyses, they were evaluated separately. Adjusted odds ratios (aORs) were calculated using conditional logistic regression to assess the association with VPI use (sorafenib, sunitinib, and pazopanib) considering various VPI exposure windows and cumulative use. A total of 1461 cases were included (mean [SD] age, 73.0 [12.3] years; 1118 male patients [76.5%]), matched to 7198 controls. AA or AD risk increased with a VPI exposure of 100 days or less before the index date (aOR, 2.10; 95% CI, 1.40-3.15), mainly from VPI-associated AD (aOR, 3.09; 95% CI, 1.77-5.39). Longer VPI duration (68 days or more: aOR, 2.64; 95% CI, 1.66-4.19) and higher cumulative dose (61 or more defined daily doses: aOR, 2.65; 95% CI, 1.66-4.23) increased the risk. The use of the 3 study VPIs (sorafenib, sunitinib, and pazopanib) was associated with an increased risk of AA and AD in patients with cancer, essentially all of the risk from VPI-associated AD. Future studies are needed to determine the risk factors of VPI-associated AA and AD, as well as to establish a class effect.

Molecular Mechanisms Underlying Vascular Remodeling in Hypertension.

Hypertension, a common cardiovascular disease, is primarily characterized by vascular remodeling. Recent extensive research has led to significant progress in understanding its mechanisms. Traditionally, vascular remodeling has been described as a unidirectional process in which blood vessels undergo adaptive remodeling or maladaptive remodeling. Adaptive remodeling involves an increase in vessel diameter in response to increased blood flow, while maladaptive remodeling refers to the narrowing or thickening of blood vessels in response to pathological conditions. However, recent research has revealed that vascular remodeling is much more complex. It is now understood that vascular remodeling is a dynamic interplay between various cellular and molecular events. This interplay process involves different cell types, including endothelial cells, smooth muscle cells, and immune cells, as well as their interactions with the extracellular matrix. Through these interactions, blood vessels undergo intricate and dynamic changes in structure and function in response to various stimuli. Moreover, vascular remodeling involves various factors and mechanisms such as the renin-angiotensin-aldosterone system (RAS), oxidative stress, inflammation, the extracellular matrix (ECM), sympathetic nervous system (SNS) and mechanical stress that impact the arterial wall. These factors may lead to vascular and circulatory system diseases and are primary causes of long-term increases in systemic vascular resistance in hypertensive patients. Additionally, the presence of stem cells in adventitia, media, and intima of blood vessels plays a crucial role in vascular remodeling and disease development. In the future, research will focus on examining the underlying mechanisms contributing to hypertensive vascular remodeling to develop potential solutions for hypertension treatment. This review provides us with a fresh perspective on hypertension and vascular remodeling, undoubtedly sparking further research efforts aimed at uncovering more potent treatments and enhanced preventive and control measures for this disease.

Xanthine Oxidoreductase in the Pathogenesis of Endothelial Dysfunction: An Update.

Xanthine oxidoreductase (XOR) is a rate-limiting enzyme in the formation of uric acid (UA) and is involved in the generation of reactive oxygen species (ROS). Overproduction of ROS has been linked to the pathogenesis of hypertension, atherosclerosis, and cardiovascular disease, with multiple studies over the last 30 years demonstrating that XOR inhibition is beneficial. The involvement of XOR and its constituents in the advancement of chronic inflammation and ROS, which are responsible for endothelial dysfunction, is the focus of this evidence-based review. An overabundance of XOR products and ROS appears to drive the inflammatory response, resulting in significant endothelium damage. It has also been demonstrated that XOR activity and ED are connected. Diabetes, hypertension, and cardiovascular disease are all associated with endothelial dysfunction. ROS mainly modifies the activity of vascular cells and can be important in normal vascular physiology as well as the development of vascular disease. Suppressing XOR activity appears to decrease endothelial dysfunction, probably because it lessens the generation of reactive oxygen species and the oxidative stress brought on by XOR. Although there has long been a link between higher vascular XOR activity and worse clinical outcomes, new research suggests a different picture in which positive results are mediated by XOR enzymatic activity. Here in this study, we aimed to review the association between XOR and vascular endothelial dysfunction. The prevention and treatment approaches against vascular endothelial dysfunction in atherosclerotic disease.

Does SarsCoV-2 infection really cause damage to retinal microcirculation in mild cases of COVID-19?

Aim To evaluate changes of retinal microcirculation in mild cases of recovered COVID-19 patients at least three months after the infection by optical coherence tomography angiography (OCTA) non-invasive method. Methods In this prospective cross-sectional study, 50 right eyes of 50 recovered COVID-19 patients were compared with 50 right eyes of age and gender-matched healthy controls. After the complete ophthalmological examination, all participants underwent OCTA measurements (RTVue XR Avanti, Optovue, Fremont, CA, USA). Results The time between the initial onset of symptoms, and ophthalmologic examination was 479.20 ±197.10 (126-754) days. Findings of ophthalmic examination of all eyes of the recovered COVID-19 patients were within normal range. Significantly reduced superficial (p=0.046) and deep (p=0.044) macular vessel density (VD) in foveal region in the eyes of the recovered COVID-19 patients was found compared with healthy controls. Significantly enlarged foveal avascular zone (FAZ) area and perimeter in the eyes of the recovered COVID-19 patients (p<0.001) were found too. Conclusion Recovered COVID-19 patients have impaired retinal microcirculation, which can be a cause of the development of retinal vascular diseases.

Phenotypic switching of vascular smooth muscle cells in atherosclerosis, hypertension, and aortic dissection.

Vascular smooth muscle cells (VSMCs) play a critical role in regulating vasotone, and their phenotypic plasticity is a key contributor to the pathogenesis of various vascular diseases. Two main VSMC phenotypes have been well described: contractile and synthetic. Contractile VSMCs are typically found in the tunica media of the vessel wall, and are responsible for regulating vascular tone and diameter. Synthetic VSMCs, on the other hand, are typically found in the tunica intima and adventitia, and are involved in vascular repair and remodeling. Switching between contractile and synthetic phenotypes occurs in response to various insults and stimuli, such as injury or inflammation, and this allows VSMCs to adapt to changing environmental cues and regulate vascular tone, growth, and repair. Furthermore, VSMCs can also switch to osteoblast-like and chondrocyte-like cell phenotypes, which may contribute to vascular calcification and other pathological processes like the formation of atherosclerotic plaques. This provides discusses the mechanisms that regulate VSMC phenotypic switching and its role in the development of vascular diseases. A better understanding of these processes is essential for the development of effective diagnostic and therapeutic strategies.

Gestational Hypoxia Impaired Endothelial Nitric Oxide Synthesis Via miR-155-5p/NADPH Oxidase/Reactive Oxygen Species Axis in Male Offspring Vessels.

Nitric oxide (NO) is the most important vasodilator secreted by vascular endothelial cells, and its abnormal synthesis is involved in the development of cardiovascular disease. The prenatal period is a critical time for development and largely determines lifelong vascular health in offspring. Given the high incidence and severity of gestational hypoxia in mid-late pregnancy, it is urgent to further explore whether it affects the long-term synthesis of NO in offspring vascular endothelial cells. Pregnant Sprague-Dawley rats were housed in a normoxic or hypoxic (10.5% O2) chamber from gestation days 10 to 20. The thoracic aortas of fetal and adult male offspring were isolated for experiments. Gestational hypoxia significantly reduces the NO-dependent vasodilation mediated by acetylcholine in both the fetal and adult offspring thoracic aorta rings. Meanwhile, acetylcholine-induced NO synthesis is impaired in vascular endothelial cells from hypoxic offspring thoracic aortas. We demonstrate that gestational hypoxic offspring exhibit a reduced endothelial NO synthesis capacity, primarily due to increased expression of NADPH oxidase 2 and enhanced reactive oxygen species. Additionally, gestational hypoxic offspring show elevated levels of miR-155-5p in vascular endothelial cells, which is associated with increased expression of NADPH oxidase 2 and reactive oxygen species generation, as well as impaired NO synthesis. The present study is the first to demonstrate that gestational hypoxia impairs endothelial NO synthesis via the miR-155-5p/NADPH oxidase 2/reactive oxygen species axis in offspring vessels. These novel findings indicate that the detrimental effects of gestational hypoxia on fetal vascular function can persist into adulthood, providing new insights into the development of vascular diseases.

Endothelial-derived microvesicles promote pro-migratory cross-talk with smooth muscle cells by a mechanism requiring tissue factor and PAR2 activation.

Microvesicles (MV) released by endothelial cells (EC) following injury or inflammation contain tissue factor (TF) and mediate communication with the underlying smooth muscle cells (SMC). Ser253-phosphorylated TF co-localizes with filamin A at the leading edge of migrating SMC. In this study, the influence of endothelial-derived TF-MV, on human coronary artery SMC (HCASMC) migration was examined. MV derived from human coronary artery EC (HCAEC) expressing TFWt accelerated HCASMC migration, but was lower with cytoplasmic domain-deleted TF. Furthermore, incubation with TFAsp253-MV, or expression of TFAsp253 in HCASMC, reduced cell migration. Blocking TF-factor VIIa (TF-fVIIa) procoagulant/protease activity, or inhibiting PAR2 signaling on HCASMC, abolished the accelerated migration. Incubation with fVIIa alone increased HCASMC migration, but was significantly enhanced on supplementation with TF. Neither recombinant TF alone, factor Xa, nor PAR2-activating peptide (SLIGKV) influenced cell migration. In other experiments, HCASMC were transfected with peptides corresponding to the cytoplasmic domain of TF prior to stimulation with TF-fVIIa. Cell migration was suppressed only when the peptides were phosphorylated at position of Ser253. Expression of mutant forms of filamin A in HCASMC indicated that the enhancement of migration by TF but not by PDGF-BB, was dependent on the presence of repeat-24 within filamin A. Incubation of HCASMC with TFWt-MV significantly reduced the levels of Smoothelin-B protein, and upregulated FAK expression. In conclusion, Ser253-phosphorylated TF and fVIIa released as MV-cargo by EC, act in conjunction with PAR2 on SMC to promote migration and may be crucial for normal arterial homeostasis as well as, during development of vascular disease.