Increased Vascular Contractility in Hypertension Results From Impaired Endothelial Calcium Signaling

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.