STIM and Orai proteins: players in sexual differences in hypertension-associated vascular dysfunction?

Sex-associated differences in hypertension have been observed repeatedly in epidemiological studies; however, the mechanisms conferring vascular protection to females are not totally elucidated. Sex-related differences in intracellular Ca²⁺ handling or, more specifically, in mechanisms that regulate Ca²⁺ entry into vascular smooth muscle cells have been identified as players in sex-related differences in hypertension-associated vascular dysfunction. Recently, new signalling components that regulate Ca²⁺ influx, in conditions of intracellular store depletion, were identified: STIM1 (stromal interaction molecule 1), which works as an intracellular Ca²⁺ sensor; and Orai1, which is a component of the CRAC (Ca²⁺ release-activated Ca²⁺) channels. Together, these proteins reconstitute store-operated Ca²⁺ channel function. Disturbances in STIM1/Orai1 signalling have been implicated in pathophysiological conditions, including hypertension. In the present article, we analyse evidence for sex-related differences in Ca²⁺ handling and propose a new hypothesis where sex-related differences in STIM/Orai signalling may contribute to hypertension-associated vascular differences between male and female subjects.