Calcium signaling in endothelial and vascular smooth muscle cells; sex differences and the influence of estrogens and androgens

Calcium signaling in vascular endothelial cells (ECs) and smooth muscle cells (VSMC) is essential for the regulation of vascular tone. However, the changes to intracellular Ca²⁺ concentrations are often influenced by sex differences. Furthermore, a large body of evidence shows that sex hormone imbalance leads to dysregulation of Ca²⁺ signaling and this is a key factor in the pathogenesis of cardiovascular diseases. In this review, the effects of estrogens and androgens on vascular calcium-handling proteins are discussed, with emphasis on the associated genomic or non-genomic molecular mechanisms. The experimental models from which data were collected were also considered. The review highlights: 1) in female ECs, TRPV4 and MCU enhances Ca²⁺-dependent NO generation. In males, only TRPC3 plays a fundamental role in this effect. 2) Female VSMCs have lower cytosolic Ca²⁺ levels than males due to differences in the activity and expression of STIM1, Orai1, Ca_V1.2, NKCC1, and the Na⁺/K⁺-ATPase. 3) When compared with androgens, the influence of estrogens on Ca²⁺ homeostasis, vascular tone and incidence of vascular disease is better documented. 4) Many studies use supraphysiological concentrations of sex hormones, which may limit the physiological relevance of outcomes. 5) Sex-dependent differences in Ca²⁺ signaling mean both sexes ought to be included in experimental design.