Abstract
Heat-shock protein 70 (HSP70) contributes to cellular calcium (Ca2+) handling mechanisms during receptor-mediated vascular contraction. Interestingly, previous studies have independently reported sex-related differences in HSP70 expression and Ca2+ dynamics. Still, it is unknown if sex, as a variable, plays a role in the impact that HSP70 has upon vascular contraction. To narrow this gap, we investigated if differences exist in the expression levels of HSP70 in the aorta, and if targeting this protein contributes to sex disparity in vascular responses. We report that, compared with male animals, female rats present a reduction in the basal levels of HSP70. More compelling, we found that the blockade of HSP70 has a greater impact on phenylephrine-induced phasic and tonic vascular contraction in female animals. In fact, it seems that the inhibition of HSP70 significantly affects vascular Ca2+ handling mechanisms in females, which could be associated with the fact that these animals have impaired HSP70 expression. Corroborating this idea, we uncovered that the higher sensitivity of female rats to HSP70 inhibition does not involve an increase in NO-dependent vasodilation nor a decrease in vascular oxidative stress. In summary, our findings reveal a novel mechanism associated with sex-specific differences in vascular responses to α-1 adrenergic stimulation, which might contribute to unraveling the network of intertwined pathways conferring female protection to (cardio)vascular diseases.
Highlights
Sex differences in cardiovascular function and dysfunction are noted in different animal models, and more importantly, cardiovascular diseases, a worldwide leading cause of death, have a higher prevalence in men and post-menopausal women, indicating a protective role for female sex hormones in this system
The female rats used in this study presented lower body mass and similar glucose levels compared with age-matched male animals (Figures 1A,B, respectively)
Vascular Relaxation To gain additional mechanistic insights into the underlying pathways contributing to this response, we investigated whether the inhibition of Heat-shock protein 70 (HSP70) would facilitate endothelium-dependent relaxation in aortas isolated from female animals
Summary
Sex differences in cardiovascular function and dysfunction are noted in different animal models, and more importantly, cardiovascular diseases, a worldwide leading cause of death, have a higher prevalence in men and post-menopausal women, indicating a protective role for female sex hormones in this system (for review, see Regitz-Zagrosek and Kararigas, 2017). It has been shown that female rats have diminished Ca2+ influx (Crews et al, 1999; Barron et al, 2002; Thompson and Khalil, 2003), which might be attributed to the fact that they have reduced levels of the STIM1/Orai complex compared with male animals (Giachini et al, 2012). It is unknown if the variable sex plays a role in the impact that HSP70 has upon vascular contraction
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