Microvascular Mechanisms Underlying Persistent Vessel Dysfunction Following Preeclampsia

 描述(申请人提供)：心血管疾病仍然是一个主要的公共卫生问题，也是美国主要的死亡原因。流行病学数据表明，其他健康的妇女在怀孕期间患先兆子痫的风险显着(2-4倍)更高，患心血管疾病的风险更大；然而，导致这种联系的机制(S)尚不清楚。关于这种联系的一个假设是，在子痫前期妊娠期间，血管内皮细胞受到不可逆转的损伤。有先兆子痫妊娠史的健康女性与有无并发症妊娠史的女性相比，动脉僵硬增加，内皮依赖性血管扩张减少，但很少(如果有的话)人体研究试图探讨这种持续性血管功能障碍的机制(S)。先兆子痫的啮齿动物模型指出血管紧张素II(Ang II)和内皮素-1(ET-1)在与先兆子痫妊娠相关的血管功能障碍中的机制作用。这些数据表明，Ang II和ET-1信号的改变可能导致先兆子痫妊娠后血管内皮依赖性血管扩张减弱和一氧化氮(NO)生物利用度降低导致过度收缩和持续性血管功能障碍。因此，该方案的首要目标是探索血管紧张素II和内皮素-1可能促进血管功能障碍的机制--包括增强的收缩和减弱的内皮依赖性扩张。我们建议利用人体皮肤循环这一具有代表性的微血管床，在产后子痫前期妊娠的妇女和正常妊娠的产后对照妇女体内研究微血管信号机制。在具体目标1中，我们假设，与有健康妊娠的妇女相比，有先兆子痫妊娠的妇女对局部皮肤加热(生理刺激)和外源性乙酰胆碱(药物刺激)的内皮依赖性血管扩张反应减弱。在特定的目标2中，我们假设有先兆子痫妊娠的妇女对外源性Ang II和ET-1有更强的血管收缩反应。此外，我们假设这些改变将由Ang II敏感性和ET-1受体信号变化下游的NO生物利用度降低所介导。用于直接将药物输送到皮肤血管床的皮内微透析，以及用于测量皮肤血流的激光多普勒流量，将被用于药物剖析导致这一人群微血管功能障碍的拟议细胞机制。这项对子痫前期后持续性微血管功能障碍的机制的全面评估直接将细胞和动物研究的功能和分子结果转化为临床人群，并将有助于对患有先兆子痫妊娠的妇女的慢性心血管风险升高的管理。

 DESCRIPTION (provided by applicant): Cardiovascular disease remains a major public health problem and is the leading cause of death in the United States. Epidemiological data have illustrated that otherwise healthy women who develop preeclampsia during pregnancy are at a significantly (2-4 times) greater risk for the development of cardiovascular disease; however the mechanism(s) responsible for this association are unclear. One immerging hypothesis for this association is irreversible endothelial damage sustained during the preeclamptic pregnancy. Healthy women with a history of preeclamptic pregnancy demonstrate increased arterial stiffness and reduced endothelium- dependent vasodilation compared to women with a history of uncomplicated pregnancy, yet few, if any, human studies have sought to investigate the mechanism(s) responsible for this persistent vessel dysfunction. Rodent models of preeclampsia point to mechanistic roles for angiotensin II (ang II) and endothelin-1(ET-1) in the vessel dysfunction associated with preeclamptic pregnancy. These data suggest that changes in ang II and ET-1 signaling may lead to a pro-constrictor milieu in which attenuated endothelium-dependent vasodilation and reduced nitric oxide (NO) bioavailability result in exaggerated constriction and persistent vessel dysfunction following preeclamptic pregnancy. Therefore, the overarching goal of this proposal is to explore the mechanisms - both augmented constriction and attenuated endothelium-dependent dilation - by which ang II and ET-1 may contribute to this vessel dysfunction. We propose to utilize the human cutaneous circulation, a representative microvascular bed, to investigate microvascular signaling mechanisms in vivo in postpartum women who have had a preeclamptic pregnancy and postpartum control women who have had a normal pregnancy. In specific aim 1 we hypothesize that women who have had a preeclamptic pregnancy will have an attenuated endothelium-dependent vasodilation response to local skin heating (physiological stimulus) and exogenous acetylcholine (pharmacological stimulus) compared to women who have had a healthy pregnancy. In specific aim 2 we hypothesize that women who have had a preeclamptic pregnancy will have a greater vasoconstrictor response to exogenous ang II and ET-1 administration. Furthermore, we hypothesize that these alterations will be mediated by decreased NO bioavailability downstream of changes in ang II sensitivity and ET-1 receptor signaling. Intradermal microdialysis for the delivery of pharmacological agents directly to the cutaneous vascular bed, coupled with laser-Doppler flux for the measurement of cutaneous blood flow, will be used to pharmacodissect the proposed cellular mechanisms contributing to microvascular dysfunction in this population. This comprehensive assessment of the mechanisms that mediate the persistent microvascular dysfunction following preeclampsia directly translates the functional and molecular findings of cell and animal studies to a clinical population and will lend insight into the management of chronic elevated CVD risk in women who have suffered a preeclamptic pregnancy.