Cellular Basis for Estrogen Effects in the RVLM

绝经后，血压和心血管风险增加。在外周，性腺类固醇通过基因组机制[通过核雌激素、孕激素和雄激素受体（er、pr和ARs）]和非基因组机制（通过膜er、pr和ARs）影响肾素-血管紧张素系统（RAS）的功能，从而参与心血管调节。这些影响可能涉及血管紧张素1 （AT1）受体数量或血浆靶向性的改变，或AT1受体相关信号机制的改变，包括NAD(P)H氧化酶。同样，在中枢神经系统中，性腺类固醇可能通过影响吻侧腹外侧髓质（RVLM）中的血管紧张素II （Ang II）的作用来影响心血管功能，这一区域对控制动脉压力至关重要。性腺激素- ras在RVLM中的相互作用

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.