In Hypertension, Global Endothelial Calcium Underlies a Protective Mechanism that Limits Arterial Vasoconstriction.
Authors: Wilson Calum , Lee Matthew David , Saunter Chris D. , Girkin John M. , McCarron John G. 
Published: June 2021

In small arteries, increased vascular reactivity contributes to the raised blood pressure that characterizes established hypertension. Endothelial function is altered in hypertension and may confer protection against the increased vascular reactivity but the precise mechanisms involved are unresolved. Here, in isolated small mesenteric arteries from hypertensive SHR (arterial BP, 190 ± 4 mmHg) and age‐matched normotensive WKY (arterial BP, 120 ± 4 mmHg) rats, the mechanisms of altered endothelial function were examined using simultaneous measurement of arterial contraction and endothelial Ca2+ signalling in large fields (~2000) of cells.At rest, average Ca2+ concentration was higher in endothelium from SHR rats, compared to that in normotensive WKY controls (n = 8 in each group). In both groups, phenylephrine (1 μM) evoked an arterial contraction that had no accompanying change in endothelial Ca2+ levels during the contraction. However, phenylephrine‐induced (1 μM) contraction was reduced in arteries from SHR, compared to WKY rats (p < 0.05; n = 5 in each group). In both normotensive and hypertensive arteries, selective disruption of endothelial Ca2+ signalling, using BAPTA‐AM (30 μM), inhibited ACh‐mediated endothelial Ca2+ signalling and artery relaxation and increased the contractions evoked by phenylephrine (n = 5 per group). After BAPTA treatment, the response to phenylephrine was normalised among groups – i.e. 1 μM phenylephrine evoked a maximal contraction in both groups. The nitric oxide synthase inhibitor L‐NAME also normalised phenylephrine‐induced contractions in pressurised arteries. These results suggest that basal, Ca2+‐dependent, nitric oxide production may be upregulated in the endothelium of SHR rats to limit arterial contractions. To explore this possibility further, local spontaneous endothelial Ca2+ signals were examined using high spatial (100X, NA = 1.4) and temporal (20 Hz) resolution imaging. In the absence of stimulation with pharmacological agents, spontaneous local Ca2+ events occurred frequently in the endothelium of blood vessels from WKY rats. These events had a wide spectrum of amplitudes and durations. A spatial map of the location and distribution of the local Ca2+ sites showed the majority of local events occurred close to junctions with smooth muscle cells to a greater extent than would be expected if the Ca2+ events initiated randomly throughout the cytoplasm (p < 0.05; n = 8 in each group). These findings suggest that the local endothelial Ca2+ rises may account for an endothelial‐dependent opposition to phenylephrine‐induced tone. However, the propensity of local Ca2+ signals was significantly decreased in arteries from SHR compared to those from WKY rats (p < 0.05; n = 8 in each group). This result suggests that alterations in local endothelial Ca2+ signal dynamics are unlikely to explain the increased endothelium‐dependent negative feedback that opposes phenylephrine‐evoked contraction in hypertension.We suggest the elevated global Ca2+ concentration in endothelial cells at rest accounts for increased NO production and suppressed phenylephrine‐evoked contraction. The increased endothelial global Ca2+ concentration may be a compensatory mechanism to offset the increased contractile responsiveness of smooth muscle cells in the hypertensive rat arteries.Support or Funding InformationThis work was funded by the Wellcome Trust (202924/Z/16/Z) and the British Heart Foundation (PG/16/54/32230; PG16/82/32439), whose support is gratefully acknowledged. C.W. is supported by a Sir Henry Wellcome Postdoctoral Research Fellowship (204682/Z/16/Z).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.