Increased Vascular Contractility in Hypertension Results From Impaired Endothelial Calcium Signaling

Abstract

Endothelial cells line all blood vessels and are critical regulators of vascular tone. In hypertension, disruption of endothelial function alters the release of endothelial-derived vasoactive factors and results in increased vascular tone. Although the release of endothelial-derived vasodilators occurs in a Ca 2+ -dependent manner, little is known on how Ca 2+ signaling is altered in hypertension. A key element to endothelial control of vascular tone is Ca 2+ signals at specialized regions (myoendothelial projections) that connect endothelial cells and smooth muscle cells. This work describes disruption in the operation of this key Ca 2+ signaling pathway in hypertension. We show that vascular reactivity to phenylephrine is increased in hypertensive (spontaneously hypertensive rat) when compared with normotensive (Wistar Kyoto) rats. Basal endothelial Ca 2+ activity limits vascular contraction, but that Ca 2+ -dependent control is impaired in hypertension. When changes in endothelial Ca 2+ levels are buffered, vascular contraction to phenylephrine increased, resulting in similar responses in normotension and hypertension. Local endothelial IP 3 (inositol trisphosphate)-mediated Ca 2+ signals are smaller in amplitude, shorter in duration, occur less frequently, and arise from fewer sites in hypertension. Spatial control of endothelial Ca 2+ signaling is also disrupted in hypertension: local Ca 2+ signals occur further from myoendothelial projections in hypertension. The results demonstrate that the organization of local Ca 2+ signaling circuits occurring at myoendothelial projections is disrupted in hypertension, giving rise to increased contractile responses.

Establishment of the circadian metabolic phenotype strategy in spontaneously hypertensive rats: a dynamic metabolomics study

“…An important feature of the SHR model is that it was originally derived from the normal WKY strain [16]. Therefore, in basic scientific research on the level of hypertension animals, WKYs are used as a normal control group for SHRs [2,[17][18][19]. Metabolomics platforms have been used to measure and identify key biomarkers related to pathological conditions.…”

Disrupted Endothelial Cell Heterogeneity and Network Organization Impairs Vascular Function in Prediabetic Obesity

“…Network-level Ca 2+ signaling was imaged using a high (0.8) numerical aperture 16X objective (~0.8 µm 2 field of view). This 16X objective also permitted quantification of vascular contractility in opened arteries using edgedetection algorithms 49 . Subcellular Ca 2+ signaling was imaged using a high (1.4) numerical aperture 100X objective.…”

“…In many vascular diseases (e.g. hypertension 49 ), dysfunctional endothelium-mediated responses arise from impaired signaling between endothelial and smooth muscle cells. Such signaling occurs via specialized myoendothelial projections (MEPs) that extend from endothelial cells, through holes in the internal elastic lamina (IEL), to smooth muscle cells.…”

Shear stress-induced pathological changes in endothelial cells occur through Piezo1 activation of TRPV4

“…However, shear stress generated under conditions of high vascular pressure or turbulence has adverse effects on the cytoskeleton which can lead to increased endothelial cell stiffness, vascular permeability, and transmigration of leukocytes (1,11,39,40). We analyzed F-actin fiber distribution using F-actin plot profiling in which the intensity and orientation of F-actin fibers are measured ( Fig.…”

“…High sustained [Ca 2+ ]i, leading to calcium overload, alters normal calcium signaling pathways and causes cytoskeletal disorganization and AJs disassembly.Together these processes facilitate transendothelial migration of leukocytes.High blood pressure and shear stress also have been associated with endothelial dysfunction(1,3,13,31,42). High blood pressure or shear stress-mediated calcium overload contributes to cytoskeletal disorganization, AJs disassembly and leukocyte transendothelial migration(2,10,11,17,29,40). However, the severity of damage is endothelium-dependent, as the sensitivity to shear stress differs between the arterial and venous systems(43).…”