The role of estrogen to protect women from cardiovascular disease remains a complicated and controversial area. In this regard, we have developed the congenic mRen (2). Lewis rat that present a marked gender difference in the development of the hypertension. Ovariectomy in the mRen (2). Lewis congenic rat produces a rapid and profound increase in blood pressure in comparison to intact mRen (2). Lewis or the ovariectomized (OVX) normotensive Lewis rats (>50 mmHg) abolishing the gender difference in blood pressure. Blood pressure was normalized by either low dose estrogen (17B-estradiol) replacement or blockade of the renin-angiotensin-aldosterone system (RAAS). The significant effect of ovariectomy to increase blood pressure in the mRen (2). Lewis strain contrasts with the lack of an effect on blood pressure following ovariectomy in the spontaneously hypertensive rat (SHR). Thus, the mRen (2). Lewis strain presents a unique and relevant model to investigate the role of estrogen in the regulation of blood pressure. The overall hypothesis of the present application is that the loss of estrogen results in elevated blood pressure due to dysregulation in the balance of both pressor [ACE-Ang II] and depressor [ACE2-Ang- (1-7)] components of the RAAS. Furthermore, this imbalance influences additional systems including the endothelin (ET), reactive oxygen (ROS) and renal nitric oxide (NOS) systems that may underlie the exaggerated blood pressure response and renal injury to increased sodium intake. The overall aims will: 1) Establish the mechanisms for alteration of blood pressure in the mRen (2). Lewis female rats focusing on the regulation of both pressor and depressor components of the circulating and intrarenal RAAS; 2) Demonstrate that loss of estrogen abrogates the inhibitory influence on the RAAS during an increase in sodium intake; 3) Determine the extent that the pressor systems ET and ROS contribute to the development and maintenance of hypertension following estrogen depletion; 4) Establish the influence of the renal depressor pathway NOS to the development of hypertension and salt-sensitivity in the estrogen depleted mRen(2).Lewis strain.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL056973-07
Application #
7070626
Study Section
General Medicine B Study Section (GMB)
Program Officer
Lin, Michael
Project Start
1996-08-15
Project End
2009-06-30
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
7
Fiscal Year
2006
Total Cost
$320,038
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
Chappell, Mark C; Al Zayadneh, Ebaa M (2017) Angiotensin-(1-7) and the Regulation of Anti-Fibrotic Signaling Pathways. J Cell Signal 2:
Brosnihan, K Bridget; Chappell, Mark C (2017) Measurement of Angiotensin Peptides: HPLC-RIA. Methods Mol Biol 1527:81-99
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
Chappell, Mark C (2016) Biochemical evaluation of the renin-angiotensin system: the good, bad, and absolute? Am J Physiol Heart Circ Physiol 310:H137-52
Alzayadneh, Ebaa M; Chappell, Mark C (2015) Nuclear expression of renin-angiotensin system components in NRK-52E renal epithelial cells. J Renin Angiotensin Aldosterone Syst 16:1135-48
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
Alzayadneh, Ebaa M; Chappell, Mark C (2014) Angiotensin-(1-7) abolishes AGE-induced cellular hypertrophy and myofibroblast transformation via inhibition of ERK1/2. Cell Signal 26:3027-35
Wilson, Bryan A; Marshall, Allyson C; Alzayadneh, Ebaa M et al. (2014) The ins and outs of angiotensin processing within the kidney. Am J Physiol Regul Integr Comp Physiol 307:R487-9
Marshall, Allyson C; Shaltout, Hossam A; Pirro, Nancy T et al. (2014) Enhanced activity of an angiotensin-(1-7) neuropeptidase in glucocorticoid-induced fetal programming. Peptides 52:74-81
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

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