STIM1/Orai1 contributes to sex differences in vascular responses to calcium in spontaneously hypertensive rats

Abstract

Sex differences in Ca2+-dependent signaling and homeostasis in the vasculature of hypertensive rats are well characterized. However, sex-related differences in store-operated calcium entry (SOCE) have been minimally investigated. We hypothesized that vascular protection in females, compared to male, reflects decreased Ca2+ mobilization due to diminished activation of Orai1/ stromal interaction molecule 1 (STIM1). In addition, we investigated if female ovariectomy affects the activation of Orai1/STIM1 pathway. Endothelium-denuded aortic rings from male and female Stroke Prone Spontaneously Hypertensive (SHRSP) and Wistar-Kyoto (WKY) rats and from ovariectomized (OVX) or sham SHRSP and WKY female rats were used to functionally evaluate Ca2+ influx-induced contractions. Compared to female, aorta from male SHRSP displayed: 1) increased contraction during Ca2+ loading period; 2) similar transient contraction during Ca2+ release from the intracellular stores; 3) increased activation of STIM1 and Orai1, as evidenced by blockade of STIM1 and Orai1 with neutralizing antibodies, which reversed sex differences in contraction during Ca2+ loading period and 4) increased expression of STIM1 and Orai1. Additionally, we found that aortas from ovariectomized SHRSP showed increased contraction during the Ca2+ loading period and increased Orai1 expression but no changes in the SR buffering capacity or STIM1 expression. These data suggest that augmented activation of STIM1/Orai1 in aortas from male SHRSP represents a mechanism that contributes to sex-related impaired control of intracellular Ca2+ levels. Furthermore, female sex-hormones may negatively modulate the STIM/Orai1 pathway, contributing to vascular protection observed in female rats.

Essential Role of Smooth Muscle STIM1 in Hypertension and Cardiovascular Dysfunction

“…showed that normotensive and spontaneously hypertensive female rats have reduced Store-operated Ca 2+ entry compared to normotensive and hypertensive males, respectively and that was due to reduced expression of Orai1 and STIM1 in females 53 . The same authors showed that when spontaneously hypertensive females were ovariectomized, aortas from these female rats showed increased contraction and enhanced Orai1 expression, with no changes in STIM1 expression, suggesting that female sex hormones may down-regulate Orai1-mediated Ca 2+ entry, thus contributing to vascular protection in females.…”

“…Since STIM1 regulates the function of all three Orai isoforms, it is likely that our current findings have major relevance to both females and males. Clearly, additional studies comparing males and females side by side, similar to those of Giachini et al , 53 would be required to conclusively address this issue.…”

Symphony of Vascular Contraction

“…32 We have proposed that sex differences in hypertension might be attributed to differences in STIM1/Orai1-mediated SOCE and intracellular calcium handling mechanisms. 72 Force generation in aortae from genetically hypertensive rats was greater in males compared to females but this difference was abolished in the presence of antibodies against STIM1 and Orai1. 72 Further, expression of these proteins was greater in male compared to female hypertensive rats.…”

“…72 Force generation in aortae from genetically hypertensive rats was greater in males compared to females but this difference was abolished in the presence of antibodies against STIM1 and Orai1. 72 Further, expression of these proteins was greater in male compared to female hypertensive rats. These studies were performed mostly in conduit arteries and the relevance of our findings to resistance vessels in the context of hypertension need to be examined.…”

Emerging roles of Orai3 in pathophysiology

“…70 An interesting observation is that Orai1 expression appears higher in males compared with females, and the suggestion that higher Orai1 levels in males might explain the known propensity of males to develop cardiovascular diseases compared with females and the well-documented protective cardiovascular effects of female sex hormones in pre-menopausal women. 71,72 Whether an increased expression of Orai3 relative to Orai1 in the cardiovascular system is a characteristic of females is unknown. If this is indeed the case, the functional outcome of Orai3 upregulation in the cardiovascular system is an important question that warrants further investigations.…”