After menopause, blood pressure and cardiovascular risk increases. In the periphery, gonadal steroids contribute to cardiovascular regulation by influencing the function of the renin-angiotensin system (RAS) through genomic [via nuclear estrogen, progesterone and androgen receptors (ERs, PRs and ARs)] and non-genomic (via membrane ERs, PRs and ARs) mechanisms. These effects may involve alterations in the number or plasrnalemmal targeting of angiotensin 1 (AT1) receptors, or in AT1 receptor-linked signaling mechanisms, including NAD(P)H oxidase. Similarly, in the CNS, gonadal steroids may influence cardiovascular function by affecting angiotensin II (Ang II) actions in the rostral ventrolateral medulla (RVLM), an area crucial for the control of arterial pressure. Gonadal steroid-RAS interactions in the RVLM may be selective for the C1 adrenergic subset of bulbospinal neurons since these neurons: (a) contain nuclear ER-alpha and AT1 receptors, and (b) are excited by Ang II. It is not known, however, whether extranuclear ERs, PRs and ARs are present and functional on RVLM C1 bulbospinal neurons or their afferents. Our central hypothesis is that estrogens, progestins and androgens differentially modulate central blood pressure regulation, in part by altering the excitability and Ang II responses of RVLM C1 bulbospinal neurons, and that these effects involve both genomic and non-genomic mechanisms. We will examine whether: (1) ERs, PRs and ARs are positioned to have genomic and/or non-genomic effects on neuronal circuits in the RVLM relevant to central cardiovascular regulation; (2) estrogens, progestins and androgens affect the function of C1 bulbospinal neurons including their responses to Ang II and glutamate; and (3) gonadal steroids influence the membrane targeting of AT1 receptors and NAD(P)H oxidase subunits in C1 neurons. These studies will be conducted in normal female rats, in female rats with Ang II-induced hypertension and in ER """"""""knock-out"""""""" female mice. Light and electron microscopic immunocytochemistry of C1 neurons, complemented by patch-clamp recording and single-cell reverse transcription polymerase chain reaction, will be used. A better understanding of gender-specific blood pressure regulation will contribute to the design of more effective therapeutic strategies for post-menopausal cardiovascular disorders.
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