Ovarian Hormone Loss and Perivascular Fat

大多数女性在一生中会因为更年期或其他原因而经历卵巢激素的丢失 择期双侧输卵管卵巢切除术、卵巢早衰或其他原因。许多研究表明 卵巢激素缺乏是发生心血管疾病(CVD)的主要危险因素，而CVD是 女性的头号死因。关于激素对心血管有益的相互矛盾的研究 替代疗法(HRT)反映了不同的HRT方案和/或不同的绝经后亚群 女人。因此，更全面地了解卵巢激素丢失和HRT对 要求妇女的心血管健康全面告知妇女关于使用 激素替代疗法，特别是因为激素替代疗法在某些女性中是禁忌的。这种加深的理解也将有助于 在妇女达到生命的这一阶段时，努力为她们制定新的治疗战略。血样 血管被血管周围脂肪组织(PVAT)包围，我们和其他人已经证明它可以调节 血管功能。越来越多的人认识到，脂肪组织具有不同的功能，取决于 脂肪库的位置。因此，我们假设PVAT将显示血管和脂肪库的特异性。 功能。我们的研究还表明，PVAT对大鼠肠系膜血管的保护作用是 卵巢切除后丢失；然而，尚不清楚是否也观察到这种卵巢激素保护的丢失 在其他血管床中，如果不是，卵巢激素调节PVAT功能的差异是否由于 血管和/或脂肪库特有的影响。我们的研究结果还表明，PVAT功能的恢复可能 降低卵巢激素丢失引起的心血管疾病的风险；然而，PVAT在HRT条件下 在卵巢激素丢失仍不清楚后，功能将得到保护。因此，阐明卵巢激素是如何 功能障碍和HRT调节PVAT活性是血管床和脂肪储备的函数，可能导致 以PVAT为靶点治疗卵巢激素所致血管功能障碍的研究进展 损失。这些研究导致了我们的总体假设，即为了在目标人群中进行HRT方案 心脏保护，必须保存PVAT对微循环中小动脉的血管保护作用 因为这些阻力血管在调节血压方面起着重要作用。目标1将决定 17B-雌二醇(E_2)和卵泡刺激素(FSH)在PVAT调节肠系膜小动脉血管中的作用 反应性和一氧化氮(NO)和超氧化物歧化酶(O2-)的产生。目标2将确定PVAT的效果 血管反应性的调节作为血管床和脂肪库的函数。探索性目标3将 识别循环外周血单个核细胞(PBMC)中与PVAT改变相关的生物标志物 在实验条件下发挥作用。我们假设，已识别的生物标记物将为临床试验提供信息 旨在优化HRT方案的组成、时间和持续时间。 好了！

Most women will experience ovarian hormone loss in their lifetime due to menopause or earlier due to other elective bilateral salpingo-oophorectomy, premature ovarian failure or other causes. Many studies indicate ovarian hormone deficiency is a major risk factor for developing cardiovascular disease (CVD) and CVD is the number one cause of death in women. Conflicting studies over the cardiovascular benefits of hormone replacement therapy (HRT) reflect differing HRT regimens and/or differing subpopulations of postmenopausal women. Thus, a fuller understanding of the biology underlying the effects of ovarian hormone loss and HRT on women’s cardiovascular health is required to comprehensively inform women's decisions regarding the use of HRT especially since HRT is contraindicated in some women. This increased understanding will also facilitate efforts towards developing new therapeutic strategies for women when they reach this point in their lives. Blood vessels are surrounded by perivascular adipose tissue (PVAT), which we and others have shown can modulate vascular function. There is a growing appreciation that adipose tissue has distinct functions depending upon the location of the adipose depot. Thus, we hypothesize that PVAT will exhibit vessel and adipose depot-specific functions. Our research also shows that the vascular protective effects of PVAT on rat mesenteric vessels are lost after ovariectomy; however, it is not known whether this loss in ovarian hormone protection is also observed in other vascular beds and if not, whether differences in ovarian hormone regulation of PVAT function is due to vessel and/or adipose depot-specific effects. Our findings also suggest that restoration of PVAT function could reduce the risk of CVD induced by ovarian hormone loss; however, the HRT conditions under which PVAT function would be protected after ovarian hormone loss remains unclear. Thus, elucidating how ovarian hormone dysfunction and HRT modulates PVAT activity as a function of vascular bed and adipose depot could lead to the development of new PVAT-focused therapeutics for treating vascular dysfunction induced by ovarian hormone loss. These studies led to our overall hypothesis that in order for an HRT regimen in a target population to be cardioprotective, it must preserve the vascular protective effects of PVAT on arterioles in the microcirculation since these resistance vessels play a major role in regulating blood pressure. Aim 1 will determine the role of 17b-estradiol (E2) and follicle stimulating hormone (FSH) in PVAT modulation of mesenteric arteriole vascular reactivity and nitric oxide (NO) and superoxide (O2-) generation. Aim 2 will determine the effect of PVAT modulation of vascular reactivity as a function of the vascular bed and adipose depot. Exploratory Aim 3 will identify biomarkers in circulating peripheral blood mononuclear cells (PBMC) that correlate with altered PVAT function under the experimental conditions. We hypothesize that identified biomarkers will inform clinical trials designed to optimize the composition, timing and duration of HRT regimens. !