Abstract
Background: stromal interacting molecule‐1 (STIM1) and endoplasmic reticulum (ER) regulate intracellular calcium for vascular function. Hypertension is associated with vascular dysfunction raising the question of whether STIM1 has any role in vascular dysfunction through ER stress and oxidative stress in hypertension.Methods & results: We used male C57/BL6, homozygous/heterozygous STIM1 knockout specifically in smooth muscle cells (STIM1SMC‐/‐, STIM1SMC‐/+), and homozygous CHOP knockout (CHOP‐/‐) mice infused with and without angiotensin II (Ang II, 400 ng/Kg/min) for 4 weeks. Hypertension development was significantly delayed in STIM1SMC‐/‐ and CHOP‐/‐ mice infused with Ang II compared to control and STIM1SMC‐/+ with Ang II. The vasoconstriction of mesenteric resistance artery and thoracic aorta in response to phenylephrine was significantly reduced only in STIM1SMC‐/‐ mice infused with and without Ang II. However, vasoconstriction to thromboxane was identical in all groups and was augmented in hypertension with low effect in STIM1SMC‐/‐ and CHOP‐/‐. The endothelium‐dependent relaxation was similar in all groups but it was impaired in the control and STIMSMC‐/+ infused with Ang II, protected in STIM1SMC‐/‐ + Ang II and rescued in CHOP‐/‐ + Ang II. The NADPH oxidase activity was elevated, while eNOS phosphorylation, cGMP and nitrite levels were reduced in control with Ang II, compared to STIM1SMC‐/‐ and CHOP‐/‐ with and without Ang II. ER stress markers were only enhanced in control infused with Ang II. The expression of STIM1 was augmented in all groups of mice infused with Ang II.Conclusions: We conclude that in hypertension, the aberrant increase in STIM1 expression causes vascular dysfunction through ER stress and increases oxidative stress‐dependent mechanisms.
Published Version
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