title: STIM1/Orai1 contributes to sex differences in vascular responses to calcium in spontaneously hypertensive rats.
abstract: Sex differences in Ca2+-dependent signalling and homoeostasis in the vasculature of hypertensive rats are well characterized. However, sex-related differences in SOCE (store-operated Ca2+ entry) have been minimally investigated. We hypothesized that vascular protection in females, compared with males, reflects decreased Ca2+ mobilization due to diminished activation of Orai1/STIM1 (stromal interaction molecule 1). In addition, we investigated whether ovariectomy in females affects the activation of the Orai1/STIM1 pathway. Endothelium-denuded aortic rings from male and female SHRSP (stroke-prone spontaneously hypertensive rats) and WKY (Wistar-Kyoto) rats and from OVX (ovariectomized) or sham female SHRSP and WKY rats were used to functionally evaluate Ca2+ influx-induced contractions. Compared with females, aorta from male SHRSP displayed: (i) increased contraction during the Ca2+-loading period; (ii) similar transient contraction during Ca2+ release from the intracellular stores; (iii) increased activation of STIM1 and Orai1, as shown by the blockade of STIM1 and Orai1 with neutralizing antibodies, which reversed the sex differences in contraction during the Ca2+-loading period; and (iv) increased expression of STIM1 and Orai1. Additionally, we found that aortas from OVX-SHRSP showed increased contraction during the Ca2+-loading period and increased Orai1 expression, but no changes in the SR (sarcoplasmic reticulum)-buffering capacity or STIM1 expression. These findings 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.
authors.affiliation: Department of Physiology, Georgia Health Sciences University, Augusta, GA, USA. fernandagiachini@yahoo.com.br
authors.forename: Fernanda R C
authors.initials: FR
authors.lastname: Giachini
authors.forename: Victor V
authors.initials: VV
authors.lastname: Lima
authors.forename: Fernando P
authors.initials: FP
authors.lastname: Filgueira
authors.forename: Anne M
authors.initials: AM
authors.lastname: Dorrance
authors.forename: Maria Helena C
authors.initials: MH
authors.lastname: Carvalho
authors.forename: Zuleica B
authors.initials: ZB
authors.lastname: Fortes
authors.forename: R Clinton
authors.initials: RC
authors.lastname: Webb
authors.forename: Rita C
authors.initials: RC
authors.lastname: Tostes
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000503:physiopathology*; D001835:Body Weight; D002118:Calcium / Q000494:pharmacology*; D015220:Calcium Channels / Q000502:physiology*; D020013:Calcium Signaling; D005260:Female; D012739:Gonadal Steroid Hormones / Q000378:metabolism; D006706:Homeostasis; D006973:Hypertension / Q000378:metabolism / Q000503:physiopathology*; D066298:In Vitro Techniques; D008297:Male; D008562:Membrane Glycoproteins / Q000502:physiology*; D000071740:ORAI1 Protein; D010052:Ovariectomy; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D012727:Sex Characteristics; D015398:Signal Transduction; D000071737:Stromal Interaction Molecule 1
chemical_list: D015220:Calcium Channels; D012739:Gonadal Steroid Hormones; D008562:Membrane Glycoproteins; D000071740:ORAI1 Protein; C532493:Orai1 protein, rat; C518857:Stim1 protein, rat; D000071737:Stromal Interaction Molecule 1; D002118:Calcium