Microvascular Mechanisms Underlying Persistent Vessel Dysfunction Following Preeclampsia

先兆子痫后持续性血管功能障碍的微血管机制

• 批准号: 9390170
• 负责人: ANNA STANHEWICZ
• 金额: $ 0.07万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-08 至 2018-09-07
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9390170
• 关键词: Acetylcholine; Agonist; Angiotensin II; Animal Model; Animals; Attenuated; Biological Availability; Blood Circulation; Blood Vessels; Blood flow; Cardiovascular Diseases; Cause of Death; Cells; Cerebrum; Chronic; Clinical; Clinical Management; Coupled; Cutaneous; Data; Development; Disease; Down-Regulation; Edema; Endothelin A Receptor; Endothelin Receptor; Endothelin-1; Endothelium; Functional disorder; Goals; Heating; Human; Hypertension; Infusion procedures; Investigation; Lasers; Lead; Life; Light; Losartan; Measurement; Mediating; Microcirculation; Microcirculatory Bed; Microdialysis; Microvascular Dysfunction; Molecular; Nitric Oxide; Pathogenesis; Peripheral; Pharmacology; Physiological; Plasma; Play; Population; Postpartum Period; Postpartum Women; Pre-Eclampsia; Pregnancy; Production; Proteinuria; Public Health; Receptor Signaling; Recording of previous events; Risk; Rodent Model; Role; Seizures; Signal Transduction; Skin; Stimulus; Time; Translating; United States; Vascular Diseases; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents; Woman; arterial stiffness; cardiovascular disorder risk; clinically significant; constriction; endothelial dysfunction; epidemiologic data; healthy pregnancy; in vivo; in vivo Model; insight; maternal hypertension; pregnancy disorder; public health relevance; receptor; response; vascular bed; vasoconstriction

 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.

 描述（由申请人提供）：心血管疾病仍然是一个主要的公共卫生问题，是美国的主要死因。流行病学数据表明，在怀孕期间发生先兆子痫的健康女性发生心血管疾病的风险显著增加（2-4倍）;然而，导致这种关联的机制尚不清楚。一个关于这种关联的假设是先兆子痫妊娠期间持续的不可逆的内皮损伤。与具有无并发症妊娠史的女性相比，具有先兆子痫妊娠史的健康女性表现出动脉僵硬度增加和内皮依赖性血管舒张减少，但很少（如果有的话）人类研究试图研究造成这种持续性血管功能障碍的机制。啮齿类动物先兆子痫模型指出血管紧张素II（angII）和内皮素-1（ET-1）在先兆子痫妊娠相关血管功能障碍中的机制作用。这些数据表明，血管紧张素II和ET-1信号的变化可能会导致一个促收缩的环境中，衰减内皮依赖性血管舒张和减少一氧化氮（NO）的生物利用度的结果在夸张的收缩和持续的血管功能障碍先兆子痫妊娠。因此，该建议的首要目标是探索机制-增强收缩和减弱内皮依赖性舒张-血管紧张素II和ET-1可能有助于这种血管功能障碍。我们建议利用人体皮肤循环，一个有代表性的微血管床，在产后妇女谁有先兆子痫怀孕和产后控制妇女谁有一个正常的怀孕，在体内微血管信号转导机制进行调查。在具体目标1中，我们假设与健康妊娠的女性相比，患有先兆子痫妊娠的女性对局部皮肤加热（生理刺激）和外源性乙酰胆碱（药理刺激）的内皮依赖性血管舒张反应减弱。在具体目标2中，我们假设患有先兆子痫妊娠的妇女对外源性血管紧张素II和ET-1的给药有更大的血管收缩反应。此外，我们假设这些变化将介导的血管紧张素II敏感性和ET-1受体信号的变化下游的NO生物利用度降低。将皮内微透析用于将药理学试剂直接递送至皮肤血管床，再加上用于测量皮肤血流的激光多普勒通量，将用于药物解剖该人群中导致微血管功能障碍的拟议细胞机制。这种对子痫前期后持续微血管功能障碍的介导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，并将深入了解患有子痫前期妊娠的女性慢性心血管疾病风险升高的管理。