Stanhewicz Anna E, Jandu Sandeep, Santhanam Lakshmi, Alexander Lacy M
From the Department of Kinesiology, Pennsylvania State University, University Park, (A.E.S., L.M.A.); and Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD (S.J., L.S.).
Hypertension. 2017 Aug;70(2):382-389. doi: 10.1161/HYPERTENSIONAHA.117.09386. Epub 2017 Jun 26.
Women who have had preeclampsia have increased cardiovascular disease risk; however, the mechanism(s) responsible for this association remain unclear. Microvascular damage sustained during a preeclamptic pregnancy may persist postpartum. The putative mechanisms mediating this dysfunction include a reduction in NO-dependent dilation and an increased sensitivity to angiotensin II. In this study, we evaluated endothelium-dependent dilation, angiotensin II sensitivity, and the therapeutic effect of angiotensin II receptor blockade (losartan) on endothelium-dependent dilation in vivo in the microvasculature of women with a history of preeclampsia (n=12) and control women who had a healthy pregnancy (n=12). We hypothesized that preeclampsia would have (1) reduced endothelium-dependent dilation, (2) reduced NO-mediated dilation, and (3) increased sensitivity to angiotensin II. We further hypothesized that localized losartan would increase endothelium-dependent vasodilation in preeclampsia. We assessed microvascular endothelium-dependent vasodilator function by measurement of cutaneous vascular conductance responses to graded infusion of acetylcholine (acetylcholine; 10-102 mmol/L) and a standardized local heating protocol in control sites and sites treated with 15 mmol/L L-NAME (-nitro-l-arginine methyl ester; NO-synthase inhibitor) or 43 µmol/L losartan. Further, we assessed microvascular vasoconstrictor sensitivity to angiotensin II (10-10 mol/L). Preeclampsia had significantly reduced endothelium-dependent dilation (-0.3±0.5 versus -1.0±0.4 log; <0.001) and NO-dependent dilation (16±3% versus 39±6%; =0.006). Preeclampsia also had augmented vasoconstrictor sensitivity to angiotensin II (-10.2±1.3 versus -8.3±0.5; =0.006). Angiotensin II type I receptor inhibition augmented endothelium-dependent vasodilation and NO-dependent dilation in preeclampsia but had no effect in healthy pregnancy. These data suggest that women who have had preeclampsia have persistent microvascular dysfunction postpartum, mediated, in part, by increased sensitivity to angiotensin II.
患有先兆子痫的女性患心血管疾病的风险增加；然而，导致这种关联的机制仍不清楚。先兆子痫妊娠期间遭受的微血管损伤可能在产后持续存在。介导这种功能障碍的假定机制包括一氧化氮（NO）依赖性舒张功能降低以及对血管紧张素II的敏感性增加。在本研究中，我们评估了有先兆子痫病史的女性（n = 12）和正常妊娠的对照女性（n = 12）体内微血管的内皮依赖性舒张功能、血管紧张素II敏感性以及血管紧张素II受体阻滞剂（氯沙坦）对内皮依赖性舒张功能的治疗效果。我们假设先兆子痫会导致：（1）内皮依赖性舒张功能降低；（2）NO介导的舒张功能降低；（3）对血管紧张素II的敏感性增加。我们进一步假设局部使用氯沙坦会增加先兆子痫患者的内皮依赖性血管舒张。我们通过测量皮肤血管对分级输注乙酰胆碱（乙酰胆碱；10 - 102 mmol/L）的传导反应以及在对照部位和用15 mmol/L L - 精氨酸甲酯（L - NAME；NO合酶抑制剂）或43 µmol/L氯沙坦处理的部位采用标准化局部加热方案，来评估微血管内皮依赖性血管舒张功能。此外，我们评估了微血管对血管紧张素II（10 - 10 mol/L）的血管收缩敏感性。先兆子痫患者的内皮依赖性舒张功能显著降低（-0.3±0.5对 -1.0±0.4 log；<0.001），NO依赖性舒张功能也降低（16±3%对39±6%；=0.006）。先兆子痫患者对血管紧张素II的血管收缩敏感性也增强（-10.2±1.3对 -8.3±0.5；=0.006）。I型血管紧张素II受体抑制可增强先兆子痫患者的内皮依赖性血管舒张和NO依赖性血管舒张，但对正常妊娠者无影响。这些数据表明，有先兆子痫病史的女性产后存在持续性微血管功能障碍，部分原因是对血管紧张素II的敏感性增加。
