Impairment of microvascular endothelial Kir2.1 channels contributes to endothelial dysfunction in human hypertension.

Hypertension is associated with decreased endothelial function through reduced contributions of nitric oxide (NO). We previously discovered that flow-induced NO production in resistance arteries of mice and humans critically depends on endothelial inwardly rectifying K (Kir2.1) channels.

Visceral adipose of obese mice inhibits endothelial inwardly rectifying K channels in a CD36-dependent fashion.

Obesity imposes deficits on adipose tissue and vascular endothelium, yet the role that distinct adipose depots play in mediating endothelial dysfunction in local arteries remains unresolved. We recently showed that obesity impairs endothelial Kir2.1 channels, mediators of nitric oxide production, in arteries of visceral adipose tissue (VAT), while Kir2.

CD8 T-cell metabolism is related to cerebrovascular reactivity in middle-aged adults.

Cerebrovascular reactivity (CVR) decreases with advancing age, contributing to increased risk of cognitive impairment; however, the mechanisms underlying the age-related decrease in CVR are incompletely understood. Age-related changes to T cells, such as impaired mitochondrial respiration, increased inflammation, likely contribute to peripheral and cerebrovascular dysfunction in animals. However, whether T-cell mitochondrial respiration is related to cerebrovascular function in humans is not known.

Membrane Cholesterol Interactions with Proteins in Hypercholesterolemia-Induced Endothelial Dysfunction.

Purpose Of Review: The goal of this review is to highlight work identifying mechanisms driving hypercholesterolemia-mediated endothelial dysfunction. We specifically focus on cholesterol-protein interactions and address specific questions related to the impact of hypercholesterolemia on cellular cholesterol and vascular endothelial function. We describe key approaches used to determine the effects of cholesterol-protein interactions in mediating endothelial dysfunction under dyslipidemic conditions.

The damaging duo: Obesity and excess dietary salt contribute to hypertension and cardiovascular disease.

Hypertension is a primary risk factor for cardiovascular disease. Cardiovascular disease is the leading cause of death among adults worldwide. In this review, we focus on two of the most critical public health challenges that contribute to hypertension-obesity and excess dietary sodium from salt (i.

Mechanotransduction and the endothelial glycocalyx: Interactions with membrane and cytoskeletal proteins to transduce force.

The endothelial glycocalyx is an extracellular matrix that coats the endothelium and extends into the lumen of blood vessels, acting as a barrier between the vascular wall and blood flowing through the vessel. This positioning of the glycocalyx permits a variety of its constituents, including the major endothelial proteoglycans glypican-1 and syndecan-1, as well as the major glycosaminoglycans heparan sulfate and hyaluronic acid, to contribute to the processes of mechanosensation and subsequent mechanotransduction following such stimuli as elevated shear stress. To coordinate the vast array of processes that occur in response to physical force, the glycocalyx interacts with a plethora of membrane and cytoskeletal proteins to carry out specific signaling pathways resulting in a variety of responses of endothelial cells and, ultimately, blood vessels to mechanical force.

New developments in translational microcirculatory research.

Microvascular disease plays a critical role in systemic end-organ dysfunction, and treatment of microvascular pathologies may greatly reduce cardiovascular morbidity and mortality. The Call for Papers collection: New Developments in Translational Microcirculatory Research highlights key advances in our understanding of the role of microvessels in the development of chronic diseases as well as therapeutic strategies to enhance microvascular function. This Mini Review provides a concise summary of these advances and draws from other relevant research to provide the most up-to-date information on the influence of cutaneous, cerebrovascular, coronary, and peripheral microcirculation on the pathophysiology of obesity, hypertension, cardiovascular aging, peripheral artery disease, and cognitive impairment.

Isolation and Identification of Vascular Endothelial Cells from Distinct Adipose Depots for Downstream Applications.

Vascular endothelial cells lining the wall of the vascular system play important roles in a variety of physiological processes, including vascular tone regulation, barrier functions, and angiogenesis. Endothelial cell dysfunction is a hallmark predictor and major driver for the progression of severe cardiovascular diseases, yet the underlying mechanisms remain poorly understood. The ability to isolate and perform analyses on endothelial cells from various vascular beds in their native form will give insight into the processes of cardiovascular disease.

Targeting Lipid-Ion Channel Interactions in Cardiovascular Disease.

General lipid-lowering strategies exhibit clinical benefit, however, adverse effects and low adherence of relevant pharmacotherapies warrants the investigation into distinct avenues for preventing dyslipidemia-induced cardiovascular disease. Ion channels play an important role in the maintenance of vascular tone, the impairment of which is a critical precursor to disease progression. Recent evidence suggests that the dysregulation of ion channel function in dyslipidemia is one of many contributors to the advancement of cardiovascular disease thus bringing to light a novel yet putative therapeutic avenue for preventing the progression of disease mechanisms.

Obesity as a premature aging phenotype - implications for sarcopenic obesity.

Obesity and aging have both seen dramatic increases in prevalence throughout society. This review seeks to highlight common pathologies that present with obesity, along with the underlying risk factors, that have remarkable similarity to what is observed in the aged. These include skeletal muscle dysfunction (loss of quantity and quality), significant increases in adiposity, systemic alterations to autonomic dysfunction, reduction in nitric oxide bioavailability, increases in oxidant stress and inflammation, dysregulation of glucose homeostasis, and mitochondrial dysfunction.

Differential effects of obesity on visceral versus subcutaneous adipose arteries: role of shear-activated Kir2.1 and alterations to the glycocalyx.

Obesity imposes well-established deficits to endothelial function. We recently showed that obesity-induced endothelial dysfunction was mediated by disruption of the glycocalyx and a loss of Kir channel flow sensitivity. However, obesity-induced endothelial dysfunction is not observed in all vascular beds: visceral adipose arteries (VAAs), but not subcutaneous adipose arteries (SAAs), exhibit endothelial dysfunction.

Cholesterol-Induced Suppression of Endothelial Kir Channels Is a Driver of Impairment of Arteriolar Flow-Induced Vasodilation in Humans.

Dyslipidemia-induced endothelial dysfunction is an important factor in the progression of cardiovascular disease; however, the underlying mechanisms are unclear. Our recent studies demonstrated that flow-induced vasodilation (FIV) is regulated by inwardly rectifying K channels (Kir2.1) in resistance arteries.

Cardiovascular mechanosensitive ion channels-Translating physical forces into physiological responses.

Cells and tissues are constantly exposed to mechanical stress. In order to respond to alterations in mechanical stimuli, specific cellular machinery must be in place to rapidly convert physical force into chemical signaling to achieve the desired physiological responses. Mechanosensitive ion channels respond to such physical stimuli in the order of microseconds and are therefore essential components to mechanotransduction.

The physiological benefits of sitting less and moving more: Opportunities for future research.

Sedentary behavior (SB) and physical activity (PA) are important risk factors of cardiovascular disease morbidity and mortality. In addition to increasing the amount of moderate-to-vigorous PA (MVPA), the current PA guidelines recommend that adults should reduce SB, or any waking activity performed while sitting, reclining, or lying, with low energy expenditure. While mounting evidence has emphasized the benefits of increasing MVPA, little has focused on the effect of SB on health.

Endothelial inwardly-rectifying K channels as a key component of shear stress-induced mechanotransduction.

It has been recognized for decades that fluid shear stress plays a major role in vascular function. Acting on the endothelium shear stress induces vasorelaxation of resistance arteries and plays a major role in the propensity of the major arteries to atherosclerosis. Many elements of shear-induced signaling have been identified yet we are just beginning to decipher the roles that mechanosensitive ion channels may play in the signaling pathways initiated by shear stress.

LDL induces cholesterol loading and inhibits endothelial proliferation and angiogenesis in Matrigels: correlation with impaired angiogenesis during wound healing.

Hypercholesterolemia is a major risk factor for adverse cardiovascular outcomes, but its effect on angiogenesis and wound healing is not well understood. In this study, using a combination of mass spectrometry and laurdan two-photon imaging, we show that elevated levels of low-density lipoprotein (LDL), like those seen in hypercholesterolemic patients, lead to an increase in both free cholesterol and cholesterol esters, as well as increase in lipid order of endothelial cell membranes. Notably, these effects are distinct and opposite to the lack of cholesterol loading and the disruption of lipid order observed in our earlier studies in response to oxidized LDL (oxLDL).

Electrophysiological Recordings of Single-cell Ion Currents Under Well-defined Shear Stress.

Fluid shear stress is well known to play a major role in endothelial function. In most vascular beds, elevated shear stress from acute increases in blood flow triggers a signaling cascade resulting in vasodilation thereby alleviating mechanical stress on the vascular wall. The pattern of shear stress is also well known to be a critical factor in the development of atherosclerosis with laminar shear stress being atheroprotective and disturbed shear stress being pro-atherogenic.

Shear-Stress Sensitive Inwardly-Rectifying K Channels Regulate Developmental Retinal Angiogenesis by Vessel Regression.

Background/aims: Shear stress plays major roles in developmental angiogenesis, particularly in blood vessel remodeling and maturation but little is known about the shear stress sensors involved in this process. Our recent study identified endothelial Kir2.1 channels as major contributors to flow-induced vasodilation, a hallmark of the endothelial flow response.

Comparative analysis of endothelial cell and sub-endothelial cell elastic moduli in young and aged mice: Role of CD36.

Objective: To perform comparative analysis of the role of scavenger receptor CD36 on endothelial vs. sub-endothelial elastic modulus (stiffness) in the aortas of young and aged mice.

Approaches And Results: Elastic moduli of endothelial and sub-endothelial layers of freshly isolated mouse aortas were quantified using atomic force microscopy.

Hypercholesterolemia-Induced Loss of Flow-Induced Vasodilation and Lesion Formation in Apolipoprotein E-Deficient Mice Critically Depend on Inwardly Rectifying K Channels.

Background: Hypercholesterolemia-induced decreased availability of nitric oxide (NO) is a major factor in cardiovascular disease. We previously established that cholesterol suppresses endothelial inwardly rectifying K (Kir) channels and that Kir2.1 is an upstream mediator of flow-induced NO production.