Development Of Vascular Dysfunction Research Articles

Abstract 2064: Identifying A Novel Protein Protecting Against Atherosclerosis And Vascular Dysfunction

Atherosclerosis and ischemic heart disease are the leading causes of death in the US. The onset of atherosclerosis begins with endothelial dysfunction and ultimately progresses to occlusive plaques by mechanisms that are still incompletely understood. The basic mechanisms of atherosclerosis involve lipid accumulation and immune activation in the vascular wall. These processes are highly regulated, poorly understood, and lead to inflammation and atherosclerotic plaques in the arterial wall. We recently identified that Fat-Specific Protein 27 (FSP27) plays an important role in regulating vascular function. Using both clinical approaches that involved human biospecimens and “humanized” murine models of endothelium-specific FSP27-overexpressing transgenic (E-FSP27tg) mice, we demonstrated that FSP27 protects against high-fat diet (HFD)-induced dyslipidemia, endothelial dysfunction, and vasomotor impairment. We next hypothesized that FSP27 plays a critical role in protecting against atherosclerosis primarily via its action on endothelial cells. To test our hypothesis, we generated an innovative mouse model expressing the human FSP27 transgene specifically in the vascular endothelial cells of atherosclerosis-prone Apoe -/- mice, Apoe -/- -E-FSP27tg. Our preliminary data show that high-fat-high-cholesterol fed Apoe -/- -E-FSP27tg mice are strongly protected against plaque formation in numerous vascular territories including carotids and aorta upon feeding high-fat, high-cholesterol diets. Mechanistically, we found that FSP27 protects against oxidative stress and inflammation in the endothelial cells. Overall, our study discovered the novel beneficial cardiovascular effects of FSP27 where it protects against the development of vascular dysfunction, inflammation, and atherosclerosis.

PO3_02. Bioflavonoid luteolin attenuates pathways implicated in development of vascular dysfunction in preeclampsia

PO3_02. Bioflavonoid luteolin attenuates pathways implicated in development of vascular dysfunction in preeclampsia

Role of Altered Metabolism of Triglyceride-Rich Lipoprotein Particles in the Development of Vascular Dysfunction in Systemic Lupus Erythematosus

Impaired lipid metabolism contributes to accelerated inflammatory responses in addition to promoting the formation of atherosclerosis in systemic lupus erythematosus (SLE). We aimed to evaluate the lipid profile, inflammatory markers, and vascular diagnostic tests in active SLE patients to clarify the association between dyslipidemia and early vascular damage. 51 clinically active SLE patients and 41 age- and gender-matched control subjects were enrolled in the study. Lipoprotein subfractions were detected by Lipoprint. Brachial artery flow-mediated dilation and common carotid intima-media thickness were detected by ultrasonography. Arterial stiffness indicated by augmentation index (Aix) and pulse wave velocity was measured by arteriography. We found significantly higher Aix, higher VLDL ratio, plasma triglyceride, ApoB100, and small HDL, as well as lower HDL-C, large HDL, and ApoA1 in patients with SLE. There was a significant positive correlation of Aix with triglyceride, VLDL, IDL-C, IDL-B, and LDL1. A backward stepwise multiple regression analysis showed IDL-C subfraction to be the best predictor of Aix. Our results indicate that in young patients with SLE, triglyceride-rich lipoproteins influence vascular function detected by Aix. These parameters may be assessed and integrated into the management plan for screening cardiovascular risk in patients with SLE.

Mitochondrial-targeted antioxidant supplementation for improving age-related vascular dysfunction in humans: A study protocol.

Background: Cardiovascular disease (CVD) is the leading cause of death worldwide and aging is the primary risk factor for the development of CVD. The increased risk of CVD with aging is largely mediated by the development of vascular dysfunction. Excessive production of mitochondrial reactive oxygen species (mtROS) is a key mechanism of age-related vascular dysfunction. Therefore, establishing the efficacy of therapies to reduce mtROS to improve vascular function with aging is of high biomedical importance. Previously, in a small, randomized, crossover-design pilot clinical trial, our laboratory obtained initial evidence that chronic oral supplementation with the mitochondrial-targeted antioxidant MitoQ improves vascular function in healthy older adults. Here, we describe the protocol for an ongoing R01-funded phase IIa clinical trial to establish the efficacy of MitoQ as a therapy to improve vascular function in older adults (ClinicalTrials.gov Identifier: NCT04851288). Outcomes: The primary outcome of the study is nitric oxide (NO)-mediated endothelium-dependent dilation (EDD) as assessed by brachial artery flow-mediated dilation (FMDBA). Secondary outcomes include mtROS-mediated suppression of EDD, aortic stiffness as measured by carotid-femoral pulse wave velocity, carotid compliance and β-stiffness index, and intima media thickness. Other outcomes include the assessment of endothelial mitochondrial health and oxidative stress in endothelial cells obtained by endovascular biopsy; the effect of altered circulating factors following MitoQ treatment on endothelial cell NO bioavailability and whole cell and mitochondrial reactive oxygen species production ex vivo; and circulating markers of oxidative stress, antioxidant status, and inflammation. Methods: We are conducting a randomized, placebo-controlled, double-blind, parallel group, phase IIa clinical trial in 90 (45/group) healthy older men and women 60 years of age or older. Participants complete baseline testing and are then randomized to either 3 months of oral MitoQ (20 mg; once daily) or placebo supplementation. Outcome measures are assessed at the midpoint of treatment, i.e., 6 weeks, and again at the conclusion of treatment. Discussion: This study is designed to establish the efficacy of chronic supplementation with the mitochondrial-targeted antioxidant MitoQ for improving vascular endothelial function and reducing large elastic artery stiffness in older adults, and to investigate the mechanisms by which MitoQ supplementation improves endothelial function.

Favorable effect of rivaroxaban against vascular dysfunction in diabetic mice by inhibiting NLRP3 inflammasome activation.

Cardiovascular disease (CVD) is the leading cause of death in various complications of type 2 diabetes mellitus (T2DM). Rivaroxaban (Xarelto; Bayer), an oral direct factor Xa (FXa) inhibitor, prevents the activation of the coagulation cascade in CVD. Considering its anticoagulant and anti-inflammatory effects, we assessed the hypothesis that rivaroxaban treatment may attenuate the vascular lesion and dysfunction in T2DM mice.C57BL/6, BKS-db/db, BKS-db/+, wild-type (WT), and NLRP3-/- mice were fed with standard chow or high-fat diet (HFD). Biochemical indexes, vascular lesions, and protein expression were evaluated using Western blot analysis, immunofluorescent staining, and RNA interference. Rivaroxaban presented favorable protection of vascular dysfunction in T2DM mice with significantly relieved vascular tension, intima-media thickness, and collagen deposition. Similar improvements in NLR family pyrin domain containing 3 (NLRP3) knockout groups and rivaroxaban pointed to the positive role of rivaroxaban against vascular dysfunction in diabetic mice by ameliorating NLRP3 inflammasome activation. Furthermore, the augmentation of inflammation and cell dysfunction in mice aortic endothelial cells (MAECs) and smooth muscle cells (MOVASs) induced by soluble FXa may be blocked by rivaroxaban via protease-activated receptors (PAR-1, PAR-2), mitogen-activated protein kinase (MAPK), and nuclear factor κ-B (NF-κB) pathway.The data indicate that the development of vascular dysfunction and inflammation in T2DM mice may be blocked by rivaroxaban in vivo and in vitro. Rivaroxaban treatment may also attenuate NLRP3 inflammasome activation via PARs, MAPK, and NF-κB pathway. This study provides mechanistic evidence of rivaroxaban therapies for vascular complications of T2DM.

Characterization of Systemic and Regional Hemodynamics and Vascular Dysfunction in Mice with Fecal Induced Peritonitis.

Sepsis is associated with circulatory dysfunction contributing to disturbed blood flow and organ injury. Decreased organ perfusion in sepsis is attributed, in part, to the loss of vasoregulatory mechanisms. Identifying which vascular beds are most susceptible to dysfunction is important for monitoring the recovery of organ function and guiding interventions. This study aimed to investigate the development of vascular dysfunction as sepsis progressed to septic shock. Anesthetized C57Bl/6 mice were instrumented with a fiberoptic pressure sensor in the carotid artery for blood pressure measurements. In subgroups of mice, regional blood flow measurements were taken by positioning a perivascular flow probe around either the left carotid, left renal, or superior mesenteric arteries. Hemodynamic parameters and their responsiveness to bolus doses of vasoactive drugs were recorded prior to and continuously after injection of fecal slurry (1.3 mg/g body weight) for 4 h. Fecal slurry-induced peritonitis reduced mean arterial pressure (62.7 ± 2.4 mmHg vs. 37.5 ± 3.2 mmHg in vehicle and septic mice, respectively), impaired cardiac function, and eventually reduced organ blood flow (71.9%, 66.8%, and 65.1% in the superior mesenteric, renal, and carotid arteries, respectively). The mesenteric vasculature exhibited dysregulation before the renal and carotid arteries, and this underlying dysfunction preceded the blood pressure decline and impaired organ blood flow.

High Soluble Endoglin Levels Affect Aortic Vascular Function during Mice Aging.

Endoglin is a 180 kDa transmembrane glycoprotein that was demonstrated to be present in two different endoglin forms, namely membrane endoglin (Eng) and soluble endoglin (sEng). Increased sEng levels in the circulation have been detected in atherosclerosis, arterial hypertension, and type II diabetes mellitus. Moreover, sEng was shown to aggravate endothelial dysfunction when combined with a high-fat diet, suggesting it might be a risk factor for the development of endothelial dysfunction in combination with other risk factors. Therefore, this study hypothesized that high sEng levels exposure for 12 months combined with aging (an essential risk factor of atherosclerosis development) would aggravate vascular function in mouse aorta. Male transgenic mice with high levels of human sEng in plasma (Sol-Eng+) and their age-matched male transgenic littermates that do not develop high soluble endoglin (Control) on a chow diet were used. The aging process was initiated to contribute to endothelial dysfunction/atherosclerosis development, and it lasted 12 months. Wire myograph analysis showed impairment contractility in the Sol-Eng+ group when compared to the control group after KCl and PGF2α administration. Endothelium-dependent responsiveness to Ach was not significantly different between these groups. Western blot analysis revealed significantly decreased protein expression of Eng, p-eNOS, and ID1 expression in the Sol-Eng+ group compared to the control group suggesting reduced Eng signaling. In conclusion, we demonstrated for the first time that long-term exposure to high levels of sEng during aging results in alteration of vasoconstriction properties of the aorta, reduced eNOS phosphorylation, decreased Eng expression, and altered Eng signaling. These findings suggest that sEng can be considered a risk factor for the development of vascular dysfunction during aging and a potential therapeutical target for pharmacological intervention.

Abstract P281: Vascular Remodeling And Impaired Vascular Smooth Muscle Cell Plasticity In Age And Sex-dependent Hypertension

Aim: Hypertension (HTN) and aging are associated with the development of vascular dysfunction. We speculated that vascular smooth muscle cell plasticity and vascular remodeling play major roles in age and sex-dependent HTN. Methods: Male and female Sprague-Dawley (SD) rats aged 3 and 16-months-old (N=6/group) were housed under standard conditions. Blood pressure was measured via femoral artery cannulation and sympathetic tone to the vasculature was estimated by ganglion blockade via Hexamethonium (30mg/Kg IV). PBS-perfused abdominal aorta and renal arteries were collected and immunoblotting was performed following protein extraction. Results: Male SD rats, but not females, develop HTN and increased sympathetic tone with age. Aged hypertensive male rats, but not aged normotensive females, exhibit reduced p-Erk1/2 and p-eNos levels in both abdominal aorta and renal arteries. α-Smooth Muscle Actin significantly increased in aged male abdominal aorta. Elevated c-Src was observed in aged female abdominal aorta and p-c-Src was reduced in aged male abdominal aorta. Caveolin-1 changed oppositely in young and aged abdominal aorta and renal arteries of two sexes. Conclusions: Our data suggest that artery-specific changes of key signaling molecules contribute to impaired vascular smooth muscle plasticity and vascular dysfunction in aged hypertensive male but not in aged normotensive female rats.

FKBPL and SIRT-1 Are Downregulated by Diabetes in Pregnancy Impacting on Angiogenesis and Endothelial Function.

Diabetes in pregnancy is associated with adverse pregnancy outcomes including preterm birth. Although the mechanisms leading to these pregnancy complications are still poorly understood, aberrant angiogenesis and endothelial dysfunction play a key role. FKBPL and SIRT-1 are critical regulators of angiogenesis, however, their roles in pregnancies affected by diabetes have not been examined before in detail. Hence, this study aimed to investigate the role of FKBPL and SIRT-1 in pre-gestational (type 1 diabetes mellitus, T1D) and gestational diabetes mellitus (GDM). Placental protein expression of important angiogenesis proteins, FKBPL, SIRT-1, PlGF and VEGF-R1, was determined from pregnant women with GDM or T1D, and in the first trimester trophoblast cells exposed to high glucose (25 mM) and varying oxygen concentrations [21%, 6.5%, 2.5% (ACH-3Ps)]. Endothelial cell function was assessed in high glucose conditions (30 mM) and following FKBPL overexpression. Placental FKBPL protein expression was downregulated in T1D (FKBPL; p<0.05) whereas PlGF/VEGF-R1 were upregulated (p<0.05); correlations adjusted for gestational age were also significant. In the presence of GDM, only SIRT-1 was significantly downregulated (p<0.05) even when adjusted for gestational age (r=-0.92, p=0.001). Both FKBPL and SIRT-1 protein expression was reduced in ACH-3P cells in high glucose conditions associated with 6.5%/2.5% oxygen concentrations compared to experimental normoxia (21%; p<0.05). FKBPL overexpression in endothelial cells (HUVECs) exacerbated reduction in tubule formation compared to empty vector control, in high glucose conditions (junctions; p<0.01, branches; p<0.05). In conclusion, FKBPL and/or SIRT-1 downregulation in response to diabetic pregnancies may have a key role in the development of vascular dysfunction and associated complications affected by impaired placental angiogenesis.

Study of new pathogenetic mechanisms of diabetic retinopathy development in patients with diabetic foot syndrome

Introduction and purpose. Diabetes is one of the underlying causes of blindness and other long-term negative consequences that significantly affect patients’ quality of life. The study aimed to determine the indicators characterizing the pathogenetic mechanisms of the development of vascular dysfunction, in particular diabetic retinopathy (DR), and the relationship of these changes with nitric oxide. Material and methods. There were 2114 patients with various surgical diseases under observation (including 1073 patients with purulent-septic soft tissue diseases), among them there were 193 patients with type 2 diabetes mellitus (DM) and 134 patients with Wagner stage 2-5 diabetic foot syndrome (DFS) and diabetic retinopathy in the main group (268 eyes). The comparison group included 59 patients (118 eyes) of the corresponding age with DM without DFS and DR. Both groups were the same in age and gender. Results. The level of the end products of nitric oxide metabolism in peripheral blood was found to be 1.78 times (p&lt;0.01) higher compared with patients without DR. A decrease in the activity of superoxide dismutase (SOD) in patients with DR was by 1.56 times (p&lt;0.01) lower relative to the comparison group. The content of thiobarbituric acid (TBA)-active products in the peripheral blood of patients of the main group exceeded by 1.58 times (p &lt;0.01) the reference values of patients without DR. When determining the content of S-nitrosithiols, an increase in these indicators in the main group was found to be 2.38 times (p&lt;0.01). Patients in the main group with DR also showed a 5.13-fold (p&lt;0.001) increase in peripheral blood homocysteine concentration. NO is known to have both positive and harmful effects depending on its concentration. On the one hand, NO causes relaxation of blood vessels by reducing blood pressure, prevents platelet aggregation and adhesion, limits LDL cholesterol oxidation, suppresses smooth muscle cell proliferation, and reduces the expression of proinflammatory genes that are associated with atherogenesis. It is known that NO can have both positive and harmful effects, depending on its concentration. On the one hand, NO causes relaxation of blood vessels, reducing blood pressure, prevents platelet aggregation and adhesion, limits the oxidation of LDL cholesterol, suppresses the proliferation of smooth muscle cells, and reduces the expression of pro-inflammatory genes that are associated with atherogenesis. On the other hand, NO interacts with O2-, leading to the inactivation of NO and the production of peroxynitrite, which post-transcriptionally modifies proteins and negatively affects their function. This can contribute to endothelial dysfunction by stimulating the production of inflammatory mediators and lipid peroxidation and thus increasing cell permeability. Conclusions. The findings show that the patients with diabetes mellitus complicated by retinopathy and DFS had a significant increase in the content of nitric oxide in the peripheral blood, the cause of which is hyperglycemia. The use of an intercellular mediator (nitric oxide), which contributes to the physiological regulation of the hemodynamics of the eye, protects vascular endothelial cells from pathogenic factors of ischemia, will help clinicians choose an effective pharmacological therapy appropriate for a particular patient and a particular eye.

Cardiovascular Outcomes in the Acute Phase of COVID-19.

The cumulative number of cases in the current global coronavirus disease 19 (COVID-19) pandemic, caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has exceeded 100 million, with the number of deaths caused by the infection having exceeded 2.5 million. Recent reports from most frontline researchers have revealed that SARS-CoV-2 can also cause fatal non-respiratory conditions, such as fatal cardiovascular events. One of the important mechanisms underlying the multiple organ damage that is now known to occur during the acute phase of SARS-CoV-2 infection is impairment of vascular function associated with inhibition of angiotensin-converting enzyme 2. To manage the risk of vascular dysfunction-related complications in patients with COVID-19, it would be pivotal to clearly elucidate the precise mechanisms by which SARS-CoV-2 infects endothelial cells to cause vascular dysfunction. In this review, we summarize the current state of knowledge about the mechanisms involved in the development of vascular dysfunction in the acute phase of COVID-19.

L-Citrulline Supplementation Increases Plasma Nitric Oxide Levels and Reduces Arginase Activity in Patients With Type 2 Diabetes.

Type 2 diabetes mellitus (T2DM) is becoming a major contributor to cardiovascular disease. One of the early signs of T2DM associated cardiovascular events is the development of vascular dysfunction. This dysfunction has been implicated in increasing the morbidity and mortality of T2DM patients. One of the important characteristics of vascular dysfunction is the impaired ability of endothelial cells to produce nitric oxide (NO). Additionally, decreases in the availability of NO is also a major contributor of this pathology. NO is produced by the activity of endothelial NO synthase (eNOS) on its substrate, L-arginine. Reduced availability of L-arginine to eNOS has been implicated in vascular dysfunction in diabetes. Arginase, which metabolizes L-arginine to urea and ornithine, competes directly with NOS for L-arginine. Hence, increases in arginase activity can decrease arginine levels, reducing its availability to eNOS and decreasing NO production. Diabetes has been linked to elevated arginase and associated vascular endothelial dysfunction. We aimed to determine levels of plasma NO and arginase activity in (T2DM) patients and the effects of L-citrulline supplementation, a natural arginase inhibitor, on inhibiting arginase activity in these patients. Levels of arginase correlated with HbA1c levels in diabetic patients. Twenty-five patients received L-citrulline supplements (2000 mg/day) for 1 month. Arginase activity decreased by 21% in T2DM patients after taking L-citrulline supplements. Additionally, plasma NO levels increased by 38%. There was a modest improvement on H1Ac levels in these patients, though not statistically significant. The effect of L-citrulline on arginase activity was also studied in bovine aortic endothelial cells (BAECs) grown in high glucose (HG) conditions. HG (25 mM, 72 h) caused a 2-fold increase in arginase activity in BAECs and decreased NO production by 30%. L-citrulline (2.5 mM) completely prevented the increase in arginase activity and restored NO production levels. These data indicate that L-citrulline can have therapeutic benefits in diabetic patients through increasing NO levels and thus maintaining vascular function possibly through an arginase inhibition related pathway.

Gut microbiota from coronary artery disease patients contributes to vascular dysfunction in mice by regulating bile acid metabolism and immune activation

BackgroundThe gut microbiota was shown to play a crucial role in the development of vascular dysfunction, and the bacterial composition differed between healthy controls and coronary artery disease patients. The goal of this study was to investigate how the gut microbiota affects host metabolic homeostasis at the organism scale.MethodsWe colonized germ-free C57BL/6 J mice with faeces from healthy control donors (Con) and coronary artery disease (CAD) patients and fed both groups a high fat diet for 12 weeks. We monitored cholesterol and vascular function in the transplanted mice. We analysed bile acids profiles and gut microbiota composition. Transcriptome sequencing and flow cytometry were performed to evaluate inflammatory and immune response.ResultsCAD mice showed increased reactive oxygen species generation and intensive arterial stiffness. Microbiota profiles in recipient mice clustered according to the microbiota structure of the human donors. Clostridium symbiosum and Eggerthella colonization from CAD patients modulated the secondary bile acids pool, leading to an increase in lithocholic acid and keto-derivatives. Subsequently, bile acids imbalance in the CAD mice inhibited hepatic bile acids synthesis and resulted in elevated circulatory cholesterol. Moreover, the faecal microbiota from the CAD patients caused a significant induction of abnormal immune responses at both the transcriptome level and through the enhanced secretion of cytokines. In addition, microbes belonging to CAD promoted intestinal inflammation by contributing to lamina propria Th17/Treg imbalance and worsened gut barrier permeability.ConclusionsIn summary, our findings elucidated that the gut microbiota impacts cholesterol homeostasis by modulating bile acids. In addition, the CAD-associated bacterial community was shown to function as an important regulator of systemic inflammation and to influence arterial stiffness.

Innate Immune Mechanisms of Arterial Hypertension and Autoimmune Disease.

The immune system is indispensable in the development of vascular dysfunction and hypertension. The interplay between immune cells and the vasculature, kidneys, heart, and blood pressure regulating nuclei in the central nervous system results in a complex and closely interwoven relationship of the immune system with arterial hypertension. A better understanding of this interplay is necessary for optimized and individualized antihypertensive therapy. Our review article focuses on innate cells in hypertension and to what extent they impact on development and preservation of elevated blood pressure. Moreover, we address the association of hypertension with chronic autoimmune diseases. The latter are ideally suited to learn about immune-mediated mechanisms in cardiovascular disease leading to high blood pressure.

Targeting mitochondrial fitness as a strategy for healthy vascular aging.

Cardiovascular diseases (CVD) are the leading cause of death worldwide and aging is the primary risk factor for CVD. The development of vascular dysfunction, including endothelial dysfunction and stiffening of the large elastic arteries (i.e., the aorta and carotid arteries), contribute importantly to the age-related increase in CVD risk. Vascular aging is driven in large part by oxidative stress, which reduces bioavailability of nitric oxide and promotes alterations in the extracellular matrix. A key upstream driver of vascular oxidative stress is age-associated mitochondrial dysfunction. This review will focus on vascular mitochondria, mitochondrial dysregulation and mitochondrial reactive oxygen species (ROS) production and discuss current evidence for prevention and treatment of vascular aging via lifestyle and pharmacological strategies that improve mitochondrial health. We will also identify promising areas and important considerations ('research gaps') for future investigation.

Hemorheological Alterations and Oxidative Damage in Sickle Cell Anemia.

Sickle cell anemia (SCA) is the most common hereditary disorder of hemoglobin (Hb) characterized by a mutation in the β globin gene, which leads to synthesis of HbS a hemoglobin which, under hypoxic conditions, gels and leading to the sickling of the red blood cells (RBC). The dehydration of the RBC increases the concentration of the intracellular Hb with an increase in the internal viscosity and consequently a decrease in the erythrocyte deformability. Sickle red blood cells due to their difficulty to flow through the microcirculation cause frequent vaso-occlusive episodes, tissue ischemia, and infarctions. Moreover, the reduced RBC deformability causes cell fragility leading to hemolysis and recently a key role of hemolysis and oxidative stress in the development of vascular dysfunction has been demonstrated. The aim of this study was to evaluate the hemorheological profiles of patients with SCA in order to point out new indices of vascular impairment, and to characterize the membrane oxidative damage of sickled RBC. Blood viscosities, erythrocyte aggregation, and viscoelastic profiles of SCA patients were determined, and the RBC oxidative damage was investigated by comparing metabolic capability and RBC membrane proteins from SCA patients with and without transfusion dependence. The hemorheological profile of SCA subjects demonstrated high blood viscosity, increased RBC aggregation, and decreased RBC deformability. These impaired flow properties were associated with RBC membrane protein oxidation, with degradation of spectrin and increased membrane-bound globin. The comparison between SCA patients with and without transfusion dependence showed metabolic and structural RBC oxidative damage significantly different.

Endothelial Dysfunction: Is There a Hyperglycemia-Induced Imbalance of NOX and NOS?

NADPH oxidases (NOX) are enzyme complexes that have received much attention as key molecules in the development of vascular dysfunction. NOX have the primary function of generating reactive oxygen species (ROS), and are considered the main source of ROS production in endothelial cells. The endothelium is a thin monolayer that lines the inner surface of blood vessels, acting as a secretory organ to maintain homeostasis of blood flow. The enzymatic production of nitric oxide (NO) by endothelial NO synthase (eNOS) is critical in mediating endothelial function, and oxidative stress can cause dysregulation of eNOS and endothelial dysfunction. Insulin is a stimulus for increases in blood flow and endothelium-dependent vasodilation. However, cardiovascular disease and type 2 diabetes are characterized by poor control of the endothelial cell redox environment, with a shift toward overproduction of ROS by NOX. Studies in models of type 2 diabetes demonstrate that aberrant NOX activation contributes to uncoupling of eNOS and endothelial dysfunction. It is well-established that endothelial dysfunction precedes the onset of cardiovascular disease, therefore NOX are important molecular links between type 2 diabetes and vascular complications. The aim of the current review is to describe the normal, healthy physiological mechanisms involved in endothelial function, and highlight the central role of NOX in mediating endothelial dysfunction when glucose homeostasis is impaired.

Overexpression of Egr‐1 contributes to the enhanced expression of Giα proteins and hyperproliferation of vascular smooth muscle cells from spontaneously hypertensive rats

Early growth response, Egr‐1, is known to activate the expression of several genes implicated in the development of vascular dysfunction. Earlier studies have shown that angiotensin II (Ang II) enhances the expression of Egr‐1 and Giα proteins in vascular smooth muscle cells (VSMC). In addition, the role of enhanced levels of endogenous Ang II has been shown to contribute to the enhanced expression of Giα proteins in spontaneously hypertensive rats (SHR). The present study was therefore undertaken to examine if VSMC from SHR also exhibit enhanced expression of Egr‐1 proteins and explore its role and underlying mechanisms in the hyperproliferation of VSMC in SHR. The levels of Egr‐1 proteins in VSMC from SHR started increasing at 2 weeks as compared to their normotensive control, WKY (Wistar‐Kyoto rats) and at 12 weeks, the levels of Egr‐1 proteins were increased significantly by 80%. The enhanced levels of Egr‐1 proteins were restored to control levels by losartan (an AT1 receptor antagonist), BQ123 (an ETA receptor antagonist), BQ788 (an ETB receptor antagonist), as well as by antioxidants, such as N‐acetyl‐L‐cysteine (NAC) and diphenyleneiodonium (DPI) but not by PD123319 (an AT2 receptor antagonist). In addition, pharmacological inhibitors of platelet‐derived growth factor (PDGF), insulin‐like growth factor (IGF) and epidermal growth factor (EGF) receptors also inhibited the overexpression of Egr‐1 proteins in VSMC from SHR. Furthermore, the enhanced expression of Egr‐1 proteins was attenuated by PD098059, an inhibitor of mitogen‐activated protein kinase (MAPK), but not by wortmannin, an inhibitor of phosphatidylinositol‐3‐kinase (PI‐3‐K). VSMC from SHR exhibit hyperproliferation which was attenuated by knocking down Egr‐1 by siRNA. In addition, siRNA of Egr‐1 also inhibited the overexpression of Giα‐2 and Giα‐3 proteins, as well as cell cycle proteins, including cyclin D1, cyclin E, cyclin dependent kinase 4 (Cdk4), Cdk2 and phosphorylated retinoblastoma protein (pRb). These results suggest that VSMC from SHR exhibit an overexpression of Egr‐1 proteins, which is attributed to the enhanced levels of endogenous Ang II and ET‐1, oxidative stress, growth factor receptors and MAPK and that the overexpression of Egr‐1, through the enhanced expression of Giα and cell cycle proteins, contributes to the hyperproliferation of VSMC from SHR.Support or Funding InformationGrant from CIHRThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Features of arterial pressure indicators in the postoperative period after surgical correction of aortic coarctation in children

Coarctation of the aorta is a congenital heart disease, which is characterized by a local narrowing of the vessel lumen. Such a congenital anomaly of the aorta requires surgical treatment. Manifestations of the disease can be diagnosed in the first day after birth as well as some patients can be asymptomatic. Clinical signs of aortic coarctation are heart failure, hypertension in the upper extremities, hypotension in the lower extremities, ischemic manifestations in the organs, hemodynamic disorders. Untimely treatment of aortic anomalies leads to complications or death of patient. The results of 24-hour blood pressure monitoring in children after surgical correction of aortic coarctation are presented in the article. Despite the successful surgical treatment of congenital aortic malformation, the long-term results of the operation are far from satisfactory. Almost 12–18 % of the patients having undergone surgery continue to be hypertensive with the vascular dysfunction development and without signs of recoarctation. Patients receive antihypertensive medications, sometimes their combinations, for a long time. Assessment of the daily blood pressure profile features in the postoperative period would help determine pathogenetic mechanisms of the hypertensive syndrome persistence and predict the pathological process course. The aim of the study was to assess the arterial pressure indices in children after successful surgical treatment of coarctation of the aorta. Materials and methods. The main group consisted of 24 children after surgical correction of aortic coarctation. The control group consisted of 20 practically healthy children. Results. A statistically significant decrease in the average diastolic blood pressure during a 24-hour period and daytime diastolic blood pressure and an increase in the daily systolic blood pressure index were determined in the main group children based on the results of 24-hour blood pressure monitoring. Conclusions: The majority of children had low general well-being in the postoperative period. Indicators of systolic and diastolic blood pressure measured by Korotkov method (83.3 %) and 24-hour blood pressure monitoring parameters were typical for hypertension in majority of patients (66.7 %). Abnormalities of the circadian profile (“non-dipper”, “over-dipper”) were detected in 50.0 % of the main group children.

Гемореологические аспекты метаболизма оксида азота в эритроцитах при развитии сосудистой дисфункции

Гемореологические аспекты метаболизма оксида азота в эритроцитах при развитии сосудистой дисфункции