Sellers, Minga Miown (2009-05). The role of estrogen receptors in the contribution of constrictor prostanoids to aortic coarctation-induced hypertension. Doctoral Dissertation.
Thesis
This study investigated the effects of selective estrogen receptor (ER) agonists on constrictor prostanoid (CP) function and on the development of mean arterial pressure (MAP) in aortic coarctation-induced hypertension (ACIH). Female Sprague-Dawley rats were divided randomly into four groups: intact (INT), ovariectomized (OVX), OVX + ER? selective agonist (4, 4', 4"-(4-Propyl-[1H]-pyrazole-1, 3, 5-triyl)trisphenol; OVX+PPT), or OVX + ER? selective agonist (2,3-bis(4-Hydroxyphenyl)-propionitrile; OVX+DPN). Rats were then subjected to abdominal aortic coarctation (hypertensive, HT) or sham surgery (normotensive, NT). PPT, DPN or vehicle treatments were given daily as a subcutaneous injection. MAP was measured every other day at 2-14 days after coarctation. Mesenteric arterioles were harvested 12-14 days after coarctation for isometric tension studies to examine concentration-responses to VP. Basal and VP-stimulated prostanoid release and mRNA and protein levels of ER? and ER? (using real time RT-PCR and immunoblotting) were measured in separate groups of arterioles. MAP was higher in INT-HT, OVX+PPT-HT and OVX+DPN-HT than in OVX-HT after 12 days. Vascular reactivity to VP was greater in OVX+PPT-NT rats than in other groups. There were no significant differences in vascular reactivity to VP in HT groups. Blockade of thromboxane receptor (TP) with SQ 29,548 (TP receptor antagonist) did not have a significant effect in any groups. Inhibition of intracellular calcium release with simvastatin (blocker of IP3 mediated calcium release) was greater in NT than in HT groups, and greater in OVX- and DPN-treated groups than in INT and PPT-treated groups. VP-stimulated release of thromboxane (TXA2) and prostacyclin (PGI2) were highest in INT-HT and OVX+PPT-HT rats. Neither mRNA nor protein expression of ERs changed significantly in response to selective ER agonist treatment or during hypertension. Selective ER? stimulation with PPT during development of ACIH resulted in similar effects to those seen in INT rats for CP release, VP reactivity of mesenteric arterioles and MAP, while selective stimulation of ER? only increased MAP. While ER? is capable of modulating most of the effects of estrogen on the vasculature, ER? has stimulatory effects on MAP during the development of ACIH that merit further investigation. Further studies of the vascular actions of ER? and ER? may lead to better hormonal therapies that successfully prevent and/or treat cardiovascular disease in post-menopausal women.
