My career goal is to secure independent NIH funding and establish a successful research program elucidating the role of the GPR30 receptor in the cardiovascular effects of estrogen. My potential to become an independent investigator not only includes scientific drive and success, evidenced by an American Heart Association postdoctoral fellowship, but also commitment to the scientific community, indicated by my work in scientific organizations such as ASPET. This transition award will allow me to acquire the additional techniques and critical thinking skills necessary for success as an independent investigator. The Hypertension and Vascular Research Center at Wake Forest University presents an optimal environment for this training due to the numerous resources available and the collegial atmosphere. These resources include not only scientific equipment and core facilities but also opportunities for teaching, interdepartmental collaboration, and professional development. My mentor, Dr. Mark Chappell, has an excellent funding record, an extensive publication record, and is well-respected among the scientific community. His excellent mentoring skills will ensure my success as an independent investigator. Premenopausal females have a lower incidence of many cardiovascular diseases, including hypertension. 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. Our laboratory utilizes the mRen2.Lewis rat, a unique angiotensin II-dependent, estrogen-sensitive, and salt-sensitive hypertensive model which appropriately reflects the higher blood pressure and salt-sensitivity seen in postmenopausal women. Our previous data show 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 II-induced vasoconstriction. These results suggest that GPR30 counteracts an activated renin-angiotensin system. G-1 also induces endothelium-independent vasorelaxation, suggesting receptor localization in vascular smooth muscle. 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 of the congenic mRen2.Lewis hypertensive animal. During the mentored year, I will determine whether GPR30 activation in mesenteric smooth muscle cells disrupts the response to angiotensin II by altering Ca2+ storage. For the independent phase, I have outlined three aims: (1) establish whether gender and estrogen status regulate vascular GPR30 and RAS component expression in the mRen2 strain.;(2) determine whether GPR30 activation in vascular smooth muscle cells alters the expression of renin-angiotensin system components and their associated functions;and (3) Assess whether high salt alters vascular GPR30 expression and whether G-1 ameliorates salt-sensitivity by altering renovascular function. These studies will establish the regulation of vascular GPR30 expression and assess its acute and chronic interaction with the renin-angiotensin system. This transition award will provide me the additional mentoring necessary to achieve future success as an independent investigator and will allow me to study a novel area of research which is clinically relevant. Information on the role of GPR30 in the cardiovascular effects of estrogen may alleviate the current controversy on hormone replacement in postmenopausal women. I am committed to maintaining financial support from institutes such as the NIH in order to sustain an independent laboratory and make significant contributions to the scientific community.

Public Health Relevance

Premenopausal females have a lower incidence of many cardiovascular diseases, including hypertension. Because this protection steeply declines after menopause, we know that estrogen has beneficial effects. There are two known estrogen receptors that mediate the long-term actions of this hormone;however, it is not known whether the newly discovered G-protein coupled receptor 30 (GPR30) contributes to estrogen's protective effects. Information on the role of GPR30 in the beneficial effects of estrogen may alleviate the current controversy on hormone replacement in postmenopausal women.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Career Transition Award (K99)
Project #
1K99HL103974-01A1
Application #
8111440
Study Section
Special Emphasis Panel (ZHL1-CSR-Z (F2))
Program Officer
Roltsch, Mark
Project Start
2011-04-15
Project End
2012-03-31
Budget Start
2011-04-15
Budget End
2012-03-31
Support Year
1
Fiscal Year
2011
Total Cost
$97,200
Indirect Cost
Name
Wake Forest University Health Sciences
Department
Surgery
Type
Schools of Medicine
DUNS #
937727907
City
Winston-Salem
State
NC
Country
United States
Zip Code
27157
Zimmerman, Margaret A; Budish, Rebecca A; Kashyap, Shreya et al. (2016) GPER-novel membrane oestrogen receptor. Clin Sci (Lond) 130:1005-16
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
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
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
Groban, Leanne; Lindsey, Sarah; Wang, Hao et al. (2012) Differential effects of late-life initiation of low-dose enalapril and losartan on diastolic function in senescent Fischer 344 x Brown Norway male rats. Age (Dordr) 34:831-43
Lindsey, Sarah H; Carver, Kyle A; Prossnitz, Eric R et al. (2011) Vasodilation in response to the GPR30 agonist G-1 is not different from estradiol in the mRen2.Lewis female rat. J Cardiovasc Pharmacol 57:598-603
Lindsey, Sarah H; Chappell, Mark C (2011) Evidence that the G protein-coupled membrane receptor GPR30 contributes to the cardiovascular actions of estrogen. Gend Med 8:343-54
Lindsey, Sarah H; Yamaleyeva, Liliya M; Brosnihan, K Bridget et al. (2011) Estrogen receptor GPR30 reduces oxidative stress and proteinuria in the salt-sensitive female mRen2.Lewis rat. Hypertension 58:665-71