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Sexual differences in STIM/Orai signaling in the vasculature of spontaneusly hypertensive rats

Abstract

A defective regulation of intracellular calcium (Ca2+) contributes to the increased sensitivity of vascular smooth muscle cells (VSMCs) to constrictor stimuli in hypertension. Stromal interaction molecule 1 (STIM1), recently identified as the Ca2+ sensor protein that triggers Ca2+ influx in response to Ca2+ store depletion, and Orai, an essential component of CRAC (Ca2+ release-activated Ca2+) channels, represent new signaling players in Ca2+ homeostasis. However, the role of these proteins in hypertension-associated vascular dysfunction is unknown. Our understanding of hypertension and the associated organ pathologies in women has lagged behind our understanding of this disease process in men, since the majority of basic science and clinical studies focusing on the mechanisms underlying hypertension have been conducted in male animals or cells and tissues derived from male subjects. Of importance, there are critical sex differences in the intrinsic mechanisms that regulate VSMC contractility, or more specifically, in Ca2+ handling mechanisms by vascular myocytes. So far no studies have addressed differences in STIM1/Orai signaling in the vasculature from male and female hypertensive animals. We will test the hypothesis that activation of STIM1/Orai, new signaling components linking intracellular Ca+2 stores to plasma membrane Ca2+ entry, is attenuated in VSMCs from female hypertensive animals compared to males. We will determine whether activation of CRAC/Orai proteins, through the Ca2+ sensor STIM1, contributes to augmented vascular contractile responses to Ca2+ in hypertension; and whether augmented activation of STIM1/Orai in the vasculature of hypertensive animals is less in females. The proposed studies, integrating physiological, pharmacological, biochemical, molecular and cellular techniques, offer an innovative research approach to better understand the effects of STIM1/Orai activation on vascular function. It will also clarify whether differential STIM1/Orai signaling contributes to sex differences in the functional vascular changes associated with arterial hypertension. Identification of causal factors and mechanisms responsible for increased vascular reactivity in arterial hypertension may avoid disease development or advance disease treatment. (AU)

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
GIACHINI, FERNANDA R. C.; LIMA, VICTOR V.; FILGUEIRA, FERNANDO P.; DORRANCE, ANNE M.; CARVALHO, MARIA HELENA C.; FORTES, ZULEICA B.; WEBB, R. CLINTON; TOSTES, RITA C. STIM 1/Orai 1 contributes to sex differences in vascular responses to calcium in spontaneously hypertensive rats. Clinical Science, v. 122, n. 5-6, p. 215-226, MAR 2012. Web of Science Citations: 15.

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