Vascular Mechanisms in Pregnancy-Induced Hypertension

描述（由申请人提供）：子痫前期是妊娠的主要并发症，以高血压（HTN）和蛋白尿为特征；然而，潜在的机制尚不清楚。妊娠后期大鼠子宫灌注压（RUPP）降低与HTN、血管收缩增加和舒张减少有关。为了寻找RUPP与HTN之间的联系机制，我们发现妊娠后期大鼠血浆肿瘤坏死因子-¿（TNF）水平升高与血管舒张降低、血管收缩和血压（BP）升高有关。此外，RUPP与血浆可溶性类膜酪氨酸激酶-1 （sFlt-1）水平升高有关，妊娠大鼠sFlt-1的慢性升高会导致血压升高。然而，涉及的中央血管靶点尚不清楚。内皮素-1 （ET-1）是一种主要的血管收缩剂，与某些形式的HTN相关，包括HTN- preg。ET-1激活血管平滑肌中的内皮素A受体（ETAR）诱导血管收缩，内皮中的ETBR诱导血管舒张物质的释放。虽然ETAR在血管收缩和HTN中的作用已被广泛研究，但血管ETBR的作用，特别是在怀孕期间，尚不清楚。我们的数据表明，与未孕大鼠相比，ET-1诱导的肠系膜微血管收缩在正常妊娠大鼠中减少，而在RUPP大鼠中增强。此外，ETBR激动剂IRL-1620和sarafotoxin c （S6c）在正常妊娠大鼠的微血管中比未孕大鼠和RUPP大鼠的微血管扩张更大，这表明ETBR介导的松弛通路在正常妊娠期间上调，而在HTN-Preg中降低。本提案的总体目标是验证ETBR是妊娠期间微血管功能和血压的重要调节因子的中心假设。在正常妊娠期间，内皮细胞ETBR的上调导致微血管舒张增强，血管收缩和血压降低。ETBR的表达/活性降低在内皮细胞功能障碍和血管收缩中起作用

DESCRIPTION (provided by applicant): Preeclampsia is a major complication of pregnancy characterized by hypertension (HTN) and proteinuria; however, the underlying mechanisms are unclear. Reduction in uterine perfusion pressure (RUPP) in late pregnant rats is associated with HTN, increased vasoconstriction and reduced relaxation. In search for the mechanisms linking RUPP to HTN, we have found that elevation of plasma levels of tumor necrosis factor-¿ (TNF¿) in late-Preg rats is associated with decreased vascular relaxation, and increased vasoconstriction and blood pressure (BP). Also, RUPP is associated with increased plasma levels of soluble fms-like tyrosine kinase-1 (sFlt-1), and chronic elevation of sFlt-1 in pregnant rats causes increases in BP. However, the central vascular targets involved are unclear. Endothelin-1 (ET-1) is a major vasoconstrictor associated with some forms of HTN including HTN-Preg. ET-1 activates endothelin A receptor (ETAR) in vascular smooth muscle to induce vasoconstriction, and ETBR in the endothelium to induce the release of vasodilator substances. Although the role of ETAR in vasoconstriction and HTN has been studied extensively, the role of vascular ETBR, particularly during pregnancy, is less clear. Our data suggest that ET-1 induced vasoconstriction is reduced in mesenteric microvessels of Norm-Preg compared to virgin rats and enhanced in RUPP rats. Also, the ETBR agonists IRL-1620 and sarafotoxin c (S6c) cause greater dilation in microvessels of Norm-Preg than virgin and RUPP rats, suggesting that ETBR-mediated relaxation pathways are upregulated during Norm-Preg and reduced in HTN-Preg. The overall objective of this proposal is to test the central hypothesis that ETBR is an important regulator of microvascular function and BP during pregnancy. During Norm-Preg, upregulation of endothelial ETBR leads to enhanced microvascular relaxation, and reduced vasoconstriction and BP. Decreased expression/activity of ETBR play a role in the endothelial cell dysfunction and vasoconstriction in HTN-Preg; and consequently, increasing the activity of ETBR should promote vasodilation and decrease BP in HTN-Preg. Studies will be performed on virgin, Norm-Preg, RUPP, TNF¿- and sFlt-1 infused pregnant Sprague-Dawley rats and ETBR-deficient mice. In addition to measuring BP, ex vivo functional studies and in vitro molecular and mechanistic studies will be performed on pressurized mesenteric and uterine microvessels. The specific aims are to test whether: 1) During Norm-Preg, upregulation of vascular ETBR leads to enhanced vascular relaxation, blunting of vasoconstriction, and reduction in BP. 2) Decreased expression/activity of ETBR play a role in the endothelial dysfunction and enhanced vasoconstriction associated with HTN-Preg. 3) Enhancing ETBR activity is a central target to promote vasodilation and reduce BP in HTN-Preg. These studies should help define the role of ETBR in enhancing vascular relaxation and reducing BP during Norm-Preg, provide a better understanding of the changes in the vascular ETBR in the pathogenesis of HTN-Preg, and highlight the potential usefulness of increasing the activity of ETBR in the management of preeclampsia.