OVARIAN REGULATION OF RESISTANCE--ARTERY DIAMETER

因心血管疾病死亡和致残的发生率 在绝经后妇女中显著增加。尽管这一影响 雌激素对脂蛋白代谢的影响已受到相当大的关注， 关于卵巢激素通过什么机制，我们知之甚少 发挥其广泛和保护血管的作用。长期的 这些研究的目标是了解通过哪些细胞通路 卵巢类固醇调节阻力动脉直径的一个主要因素 总外周阻力的决定因素，因此，全身血液 压力。我们的统一假设是卵巢类固醇，尤其是 雌激素，通过改变参与的机制来降低动脉张力 物理力量(血管内压力和流量)的传递 动脉壁的细胞(内皮、平滑肌)。通过采取 可精确控制的小动脉体外方法学的优势 无论是物理力量还是细胞外环境，都有特定的目标 是为了定量评估卵巢功能的影响，它的丧失 (外科更年期)和激素更年期(雌激素替代 治疗)对内皮细胞分泌血管活性因子的影响 跨壁压力和流量(目标1)，肌源性和 控制管腔直径的肾上腺素能机制(目标2) 血管平滑肌细胞对钙的敏感性及G的调节作用 蛋白质和蛋白激酶C(目标3)。几个创新性的实验 方法，包括串联两条血管的灌流， 细菌外毒素对细胞膜的渗透作用，以及 选择性药物干预措施的使用将在下列情况下应用 透壁压力、管腔直径和流量 同时测量和记录。通过了解卵巢是如何 类固醇通过血管壁调节机械转导，我们希望 对女性荷尔蒙通过哪些机制 降低外周阻力，预防心血管疾病。

The incidence of death and debility due to cardiovascular diseases increases markedly in post-menopausal women. Although the effects of estrogen on lipoprotein metabolism have received considerable attention, little is known about the actual mechanisms through which ovarian hormones exert their wide-ranging and protective vascular effects. The long-term goal of these studies is to understand the cellular pathways through which ovarian steroids regulate resistance artery diameter, a principal determinant of total peripheral resistance and, therefore, systemic blood pressure. Our unifying hypothesis is that ovarian steroids, particularly estrogen, reduce arterial tone by altering the mechanisms involved in the transduction of physical forces (intravascular pressure and flow) by the cells (endothelium, smooth muscle) of the arterial wall. By taking advantage of small artery in vitro methodology that allows precise control of both physical forces and extracellular environment, the specific aims are to quantitatively assess the effects of ovarian function, its loss (surgical menopause), and hormonal reinstitution (estrogen replacement therapy) on endothelial secretion of vasoactive factors in response to transmural pressure and flow (Aim 1), the interaction of myogenic and adrenergic mechanisms in the control of lumen diameter (Aim 2), and on vascular smooth muscle cell calcium sensitivity and its modulation by G proteins and protein kinase C (Aim 3). Several innovative experimental approaches, including the perfusion of two vessels in series, permeabilization of the cell membrane with a bacterial exotoxin, and the use of selective pharmacological interventions will be applied under conditions in which transmural pressure, lumen diameter and flow are simultaneously measured and recorded. By understanding how ovarian steroids modulate mechano-transduction by the vascular wall, we hope to gain new insights into the mechanisms through which female sex hormones lower peripheral resistance and protect against cardiovascular disease.