Sex differences in vascular expression and activation of STIM‐1/Orai‐1 during hypertension: focus on calcium regulation

Abstract

Sex‐related differences in Ca2+‐dependent signaling contributes to greater contractile‐responses in male hypertensive rats. We hypothesized that vascular protection in females reflects differences in Ca2+ mobilization due to differential activation of CRAC (Ca2+ release‐activated Ca2+) channels through Orai1, via its interaction with the intracellular Ca2+ sensor STIM‐1 (stromal interaction molecules). Endothelium‐denuded aortic rings from male and female stroke prone spontaneously hypertensive rats (SHRSP) and Wistar‐Kyoto (WKY) rats were used to functionally evaluate Ca2+ influx‐induced contraction. Sarcoplasmic reticulum Ca+2 ATPase was inhibited with thapsigargin (10uM). During the Ca2+ loading period: (1) force development was augmented in aortas from male SHRSP (10.0±0.9mN, n=6) vs. female (7.5±1.1mN, n=6); (2) CRAC channel blockade with 2‐APB and Gd3+ as well as (3) neutralizing antibodies against STIM‐1 and Orai‐1 normalized differences in contraction between aortas from male and female SHRSP. Expression of Orai‐1 and STIM‐1 proteins was increased in aorta from male SHRSP, vs. female SHRSP or WKY. Augmented activation of STIM‐1/Orai‐1 in aorta from male SHRSP may represent a mechanism that contributes to sex‐related impaired control of intracellular Ca2+ levels.Financial support: NIH ‐ HL71138 and HL74167