Premenopausal females tiave a lower incidence of many cardiovascular diseases, including iiypertension. Because this protection steeply declines after menopause, we know that estrogen is at least partially responsible for these beneficial effects. There are two known estrogen receptor subtypes that mediate the genomic actions of this hormone;however, it is not known whether the newly discovered G protein-coupled receptor 30 (GPR30) contributes to estrogen's cardiovascular effects. Using the mRen2.Lewis rat, a unique angiotensin ll-dependent, estrogen-sensitive, and salt-sensitive hypertensive model which appropriately reflects the higher blood pressure and salt-sensitivity seen in postmenopausal women, we showed that in vivo administration of the selective GPR30 agonist G-1 in ovariectomized females significantly reduces blood pressure, alters vascular gene expression of renin-angiotensin system components, and reduces angiotensin ll-induced vasoconstriction. We hypothesize that GPR30 exerts beneficial cardiovascular effects by opposing the actions of Ang II in vascular smooth muscle cells. Separating the actions of estrogen at GPR30 from those mediated by its nuclear estrogen receptors may elucidate the current controversy surrounding hormone replacement therapy. The proposal will take a comprehensive approach utilizing an in vitro cell culture system, an ex vivo isolated resistance vessel preparation, and in vivo analysis ofthe congenic mRen2.Lewis hypertensive animal to determine (1) whether GPR30 activation in mesenteric smooth muscle cells influences calcium mobilization; (2) whether gender and estrogen status regulates expression of GPR30 in the vasculature;(3) whether GPR30 influences the function of renin-angiotensin system components;and (4) whether a high salt diet alters vascular GPR30 expression and function. These studies will establish the regulation of'Vascular GPR30 expression and assess its acute and chronic interaction with the renin-angiotensin system.

Public Health Relevance

Premenopausal females typically have better cardiovascular health, suggesting that estrogen is beneficial. However, recent clinical trials have failed to show a benefit for hormone replacement therapy. Recently, a new site of action for estrogen named GPR30 was discovered. Information on the role of GPR30 in estrogen's effects may give us information as to the benefits and risks of hormone replacement therapy.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Transition Award (R00)
Project #
5R00HL103974-03
Application #
8529601
Study Section
Special Emphasis Panel (NSS)
Program Officer
OH, Youngsuk
Project Start
2011-04-15
Project End
2015-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
3
Fiscal Year
2013
Total Cost
$229,374
Indirect Cost
$77,664
Name
Tulane University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
053785812
City
New Orleans
State
LA
Country
United States
Zip Code
70118
Zimmerman, Margaret A; Budish, Rebecca A; Kashyap, Shreya et al. (2016) GPER-novel membrane oestrogen receptor. Clin Sci (Lond) 130:1005-16
Liu, Liu; Kashyap, Shreya; Murphy, Brennah et al. (2016) GPER activation ameliorates aortic remodeling induced by salt-sensitive hypertension. Am J Physiol Heart Circ Physiol 310:H953-61
Lovre, Dragana; Lindsey, Sarah H; Mauvais-Jarvis, Franck (2016) Effect of menopausal hormone therapy on components of the metabolic syndrome. Ther Adv Cardiovasc Dis :
Sen, Anagha; Kumar, Prerna; Garg, Renu et al. (2016) Transforming growth factor β1 antagonizes the transcription, expression and vascular signaling of guanylyl cyclase/natriuretic peptide receptor A - role of δEF1. FEBS J 283:1767-81
Yamaleyeva, Liliya M; Pulgar, Victor M; Lindsey, Sarah H et al. (2015) Uterine artery dysfunction in pregnant ACE2 knockout mice is associated with placental hypoxia and reduced umbilical blood flow velocity. Am J Physiol Endocrinol Metab 309:E84-94
Edward, Justin A; Pankey, Edward A; Jupiter, Ryan C et al. (2015) Analysis of erectile responses to bradykinin in the anesthetized rat. Am J Physiol Heart Circ Physiol 309:H499-511
Lindsey, Sarah H; Liu, Liu; Chappell, Mark C (2014) Vasodilation by GPER in mesenteric arteries involves both endothelial nitric oxide and smooth muscle cAMP signaling. Steroids 81:99-102
Zhao, Zhuo; Wang, Hao; Jessup, Jewell A et al. (2014) Role of estrogen in diastolic dysfunction. Am J Physiol Heart Circ Physiol 306:H628-40
Lindsey, Sarah H (2014) Importance of estrogen metabolites. Hypertension 64:21-2
Lindsey, Sarah H; da Silva, Ariel S; Silva, Mauro S et al. (2013) Reduced vasorelaxation to estradiol and G-1 in aged female and adult male rats is associated with GPR30 downregulation. Am J Physiol Endocrinol Metab 305:E113-8

Showing the most recent 10 out of 13 publications