Gender differences in vascular expression of endothelin and ET A/ET B receptors, but not in calcium handling mechanisms, in deoxycorticosterone acetate-salt hypertension

Abstract

We determined if the increased vascular responsiveness to endothelin-1 (ET-1) observed in male, but not in female, DOCA-salt rats is associated with differential vascular mRNA expression of ET-1 and/ or ET A /ET B receptors or with functional differences in Ca 2+ handling mechanisms by vascular myocytes. Uninephrectomized male and female Wistar rats received DOCA and drinking water containing NaCl/KCl. Control rats received vehicle and tap water. Blood pressure and contractile responses of endothelium-denuded aortic rings to agents which induce Ca 2+ influx and/or its release from internal stores were measured using standard procedures. Expression of mRNA for ET-1 and ET A /ET B receptors was evaluated by RT-PCR after isolation of total cell RNA from both aorta and mesenteric arteries. Systolic blood pressure was higher in male than in female DOCA rats. Contractions induced by Bay K8644 (which activates Ca 2+ influx through voltage-operated L-type channels), and by caffeine, serotonin or ET-1 in Ca 2+ -free buffer (which reflect Ca 2+ release from internal stores) were significantly increased in aortas from male and female DOCAsalt compared to control aortas. DOCA-salt treatment of male, but not female, rats statistically increased vascular mRNA expression of ET-1 and ET B receptors, but decreased the expression of ET A receptors. Molecular up-regulation of vascular ET B receptors, rather than differential changes in smooth muscle Ca 2+ handling mechanisms, seems to account for the increased vascular reactivity to ET-1/ET B receptor agonists and higher blood pressure levels observed in male DOCA-salt rats.

Effects of estrogen on the vascular system

“…Changes in ET Bmediated vascular responses were associated with increased ET-1 and ET B receptor gene expression in male, but not in female, animals (49). Furthermore, we observed that ovariectomy increases the vasoconstricting responses to the ET B agonist and that estrogen replacement therapy restores IRL-1620-induced responses, supporting our suggestion that the ovarian hormones modulate ET-1/ ET B receptor vascular responses/expression in DOCA-salt hypertension (50). Sexual dimorphism in vascular reactivity to ET-1 was also reported in SHR (51).…”

Testosterone induces apoptosis in vascular smooth muscle cells via extrinsic apoptotic pathway with mitochondria-generated reactive oxygen species involvement

“…Testosterone-induced production of nitric oxide (3), relaxation of various vascular beds (16,66), decrease of total cholesterol, low-density lipoprotein and triglycerides, and formation of endothelial progenitor cells (21) may account for the protective effects of the androgen in the cardiovascular system. However, reports of sudden cardiovascular death among male athletes abusing of anabolic steroids and the fact that in many experimental models of hypertension [spontaneously hypertensive rats (54), Dahl salt-sensitive rats (13), genetically hypertensive rats (1), and rats with deoxycorticosterone acetate-saltinduced hypertension (15)], males have higher levels of arterial pressure, which are abrogated by orchiectomy (9,54), indicate that testosterone is detrimental to the cardiovascular system. In addition, testosterone has been shown to directly affect many of the mechanisms that control cardiovascular function, such as the renin-angiotensin-aldosterone system, sympathetic neural activity, endothelial function, and VSMC tone (7,14,40).…”

Testosterone Induces Vascular Smooth Muscle Cell Migration by NADPH Oxidase and c-Src–Dependent Pathways

“…[1][2][3][4][5] This steroid hormone contributes not only to the development of arterial hypertension but also to hypertensionassociated vascular and renal abnormalities. 6 In humans, it is still controversial whether testosterone contributes to or protects from cardiovascular disease.…”