Increased Vascular Contractility in Hypertension Results From Impaired Endothelial Calcium Signaling.

Calum Wilson,Matthew D Lee,Charlotte Buckley,John G Mccarron,Helen R Heathcote,Xun Zhang

doi:10.1161/hypertensionaha.119.13791

Calum Wilson, Matthew D Lee + Show 4 more

Open Access

https://doi.org/10.1161/hypertensionaha.119.13791

Copy DOI

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 Ca2+-dependent manner, little is known on how Ca2+ signaling is altered in hypertension. A key element to endothelial control of vascular tone is Ca2+ signals at specialized regions (myoendothelial projections) that connect endothelial cells and smooth muscle cells. This work describes disruption in the operation of this key Ca2+ 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 Ca2+ activity limits vascular contraction, but that Ca2+-dependent control is impaired in hypertension. When changes in endothelial Ca2+ levels are buffered, vascular contraction to phenylephrine increased, resulting in similar responses in normotension and hypertension. Local endothelial IP3(inositol trisphosphate)-mediated Ca2+ signals are smaller in amplitude, shorter in duration, occur less frequently, and arise from fewer sites in hypertension. Spatial control of endothelial Ca2+ signaling is also disrupted in hypertension: local Ca2+ signals occur further from myoendothelial projections in hypertension. The results demonstrate that the organization of local Ca2+ signaling circuits occurring at myoendothelial projections is disrupted in hypertension, giving rise to increased contractile responses.

Highlights

Endothelial cells line all blood vessels and are critical regulators of vascular tone
We show that basal IP3mediated endothelial Ca2+ signaling opposes vascular tone in arteries from normotensive (Wistar Kyoto; WKY) and hypertensive rats
The magnitude of contraction induced by KCl did not differ between strains (Figure S3B; 38±3 % of initial diameter for spontaneously hypertensive rats (SHR), 45±3 % of maximum for WKY; n=4), though the maximal rate of contraction was higher in arteries from normotensive rats (Figure S3B; 2.2±0.1 % s-1 for SHR, 3.6±0.2 % s-1 for WKY; n=4)

Summary

Introduction

Endothelial cells line all blood vessels and are critical regulators of vascular tone. Localized IP3-mediated Ca2+ activity occurs spontaneously in unstimulated endothelium[23] and is amplified by extracellular agonists to limit basal and activated smooth muscle tone.[24] Of particular significance in endothelial control of vascular tone are Ca2+ signals that occur preferentially at sites where endothelial cells protrude through the internal elastic lamina (IEL) and contact smooth muscle cells (myoendothelial projections, MEPs).[23] MEPs are packed with Ca2+-activated effector proteins, including eNOS (endothelial NO synthase)[18] and the small and intermediate conductance Ca2+-sensitive potassium channels,[19] creating pivotal microdomains that are critical to the regulation of vascular function. It is unknown if local IP3-mediated Ca2+ signaling at MEPs is altered in hypertension

Methods

Results

Conclusion