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.

Public Health Relevance

Preeclampsia is a major complication of pregnancy characterized by hypertension and proteinuria, and a major cause of maternal and fetal morbidity and mortality, but the mechanisms involved are unclear. The overall objective of this proposal is to test the hypothesis that endothelin type B receptor (ETBR) is an important regulator of microvascular function not only during normal pregnancy, where an increase in endothelial ETBR leads to enhanced microvascular relaxation, and reduced vasoconstriction and blood pressure, but also in hypertension of pregnancy, where a decrease in the amount/activity of ETBR plays a role in the endothelial cell dysfunction, and increased vasoconstriction and blood pressure. The studies should help define the role of ETBR in enhancing vascular relaxation and reducing blood pressure during normal pregnancy, provide a better understanding of the changes in vascular ETBR during hypertension in pregnancy, and highlight the potential usefulness of increasing ETBR activity in the management of preeclampsia.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL065998-11A1
Application #
8506260
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Mitchell, Megan S
Project Start
2000-12-01
Project End
2017-05-31
Budget Start
2013-08-14
Budget End
2014-05-31
Support Year
11
Fiscal Year
2013
Total Cost
$408,959
Indirect Cost
$170,959
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Anwar, M A; Vorkas, P A; Li, J et al. (2016) Prolonged Mechanical Circumferential Stretch Induces Metabolic Changes in Rat Inferior Vena Cava. Eur J Vasc Endovasc Surg 52:544-552
Possomato-Vieira, J S; Khalil, R A (2016) Mechanisms of Endothelial Dysfunction in Hypertensive Pregnancy and Preeclampsia. Adv Pharmacol 77:361-431
Pojoga, Luminita H; Yao, Tham M; Opsasnick, Lauren A et al. (2015) Cooperative Role of Mineralocorticoid Receptor and Caveolin-1 in Regulating the Vascular Response to Low Nitric Oxide-High Angiotensin II-Induced Cardiovascular Injury. J Pharmacol Exp Ther 355:32-47
Garza, Amanda E; Pojoga, Luminita H; Moize, Burhanuddin et al. (2015) Critical Role of Striatin in Blood Pressure and Vascular Responses to Dietary Sodium Intake. Hypertension 66:674-80
Mata, Karina M; Li, Wei; Reslan, Ossama M et al. (2015) Adaptive increases in expression and vasodilator activity of estrogen receptor subtypes in a blood vessel-specific pattern during pregnancy. Am J Physiol Heart Circ Physiol 309:H1679-96
Mazzuca, Marc Q; Mata, Karina M; Li, Wei et al. (2015) Estrogen receptor subtypes mediate distinct microvascular dilation and reduction in [Ca2+]I in mesenteric microvessels of female rat. J Pharmacol Exp Ther 352:291-304
Shah, Dania A; Khalil, Raouf A (2015) Bioactive factors in uteroplacental and systemic circulation link placental ischemia to generalized vascular dysfunction in hypertensive pregnancy and preeclampsia. Biochem Pharmacol 95:211-26
MacColl, Elisabeth; Khalil, Raouf A (2015) Matrix Metalloproteinases as Regulators of Vein Structure and Function: Implications in Chronic Venous Disease. J Pharmacol Exp Ther 355:410-28
Ali, Sajjadh M J; Khalil, Raouf A (2015) Genetic, immune and vasoactive factors in the vascular dysfunction associated with hypertension in pregnancy. Expert Opin Ther Targets 19:1495-515
Li, Wei; Mata, Karina M; Mazzuca, Marc Q et al. (2014) Altered matrix metalloproteinase-2 and -9 expression/activity links placental ischemia and anti-angiogenic sFlt-1 to uteroplacental and vascular remodeling and collagen deposition in hypertensive pregnancy. Biochem Pharmacol 89:370-85

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