Low birth weight is associated with an increased risk for cardiovascular disease. Our laboratory has developed a unique model of placental insufficiency in the rat that results in intrauterine growth restriction (IUGR) associated with hypertension in male IUGR, but not in female IUGR. Importantly, castration abolishes hypertension in male IUGR;ovariectomy (OVX) induces a marked increase in blood pressure (BP) in female IUGR. Thus, sex hormones may mediate differences in adult IUGR BP;yet, the exact mechanism(s) remains unknown. Preliminary data suggest that renal endothelin (ET) is increased in male IUGR and in response to OVX in female IUGR;hypertension in male IUGR and OVX female IUGR is abolished by selective ETA receptor blockade. Therefore, modulation of ET by sex hormones may be critical to sex differences in IUGR BP. Preliminary data suggest oxidative stress is increased in male IUGR and OVX female IUGR. Chronic treatment with tempol, a SOD mimetic, abolishes increased oxidative stress and hypertension in male IUGR and female OVX IUGR. We report that the renin angiotensin system (RAS) plays a critical role in hypertensive IUGR;however, peripheral and intrarenal levels of the RAS are not elevated. ET can increase responsiveness to angiotensin II (ANG II);preliminary data suggest responsiveness to ANG II is increased in male IUGR and OVX female IUGR. Thus, ET induced oxidative stress and vascular responsiveness to ANG II may serve as possible mechanisms by which ET contributes to sex differences in IUGR BP. Thus, we hypothesize that testosterone increases renal vascular resistance and exacerbates hypertension in male IUGR by enhancing the endothelin system, thus leading to increased oxidative stress and vascular responsiveness to angiotensin II;and that estradiol decreases renal vascular resistance and blood pressure in female IUGR by attenuating the endothelin system, thus preventing an increase in oxidative stress and vascular responsiveness to angiotensin II. We will test the following specific aims:
Specific aim 1 : That testosterone further increases renal vascular resistance and exacerbates hypertension in male IUGR by enhancing the endothelin system;and that estradiol reduces renal vascular resistance and blood pressure in female IUGR by attenuating the endothelin system.
Specific aim 2 : That testosterone-mediated enhanced endothelin production increases oxidative stress leading to a further increase in renal vascular resistance and exacerbating hypertension in male IUGR;and that estradiol-mediated attenuation of endothelin production decreases oxidative stress leading to a reduction in renal vascular resistance and blood pressure in female IUGR.
Specific aim 3 : That testosterone-mediated enhanced endothelin production increases vascular responsiveness to angiotensin II further increasing renal vascular resistance and exacerbating hypertension in male IUGR;and that estradiol- mediated attenuation of endothelin production decreases the vascular responsiveness to angiotensin II leading to a reduction in renal vascular resistance and blood pressure in female IUGR.

Public Health Relevance

There is compelling epidemiological and experimental data which suggest that cardiovascular diseases such as hypertension may be programmed in-utero. Our laboratory utilizes a unique model of low birth weight in that rat that mimics the human condition of slow fetal growth associated with an increased risk for cardiovascular disease to investigate the mechanisms linking the birth weight and hypertension. Thus, findings from our studies may implicate preventative interventions in the health care of low birth weight individuals that may preclude the development of cardiovascular disease and hypertension.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL074927-06
Application #
7804493
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Mitchell, Megan S
Project Start
2003-12-01
Project End
2014-04-30
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
6
Fiscal Year
2010
Total Cost
$333,000
Indirect Cost
Name
University of Mississippi Medical Center
Department
Physiology
Type
Schools of Medicine
DUNS #
928824473
City
Jackson
State
MS
Country
United States
Zip Code
39216
Newsome, Ashley D; Davis, Gwendolyn K; Ojeda, Norma B et al. (2017) Complications during pregnancy and fetal development: implications for the occurrence of chronic kidney disease. Expert Rev Cardiovasc Ther 15:211-220
Davis, Gwendolyn K; Newsome, Ashley D; Ojeda, Norma B et al. (2017) Effects of Intrauterine Growth Restriction and Female Sex on Future Blood Pressure and Cardiovascular Disease. Curr Hypertens Rep 19:13
Dasinger, John Henry; Intapad, Suttira; Backstrom, Miles A et al. (2016) Intrauterine growth restriction programs an accelerated age-related increase in cardiovascular risk in male offspring. Am J Physiol Renal Physiol 311:F312-9
Dasinger, John Henry; Intapad, Suttira; Rudsenske, Benjamin R et al. (2016) Chronic Blockade of the Androgen Receptor Abolishes Age-Dependent Increases in Blood Pressure in Female Growth-Restricted Rats. Hypertension 67:1281-90
Intapad, Suttira; Dasinger, John Henry; Brown, Andrew D et al. (2016) Glucose intolerance develops prior to increased adiposity and accelerated cessation of estrous cyclicity in female growth-restricted rats. Pediatr Res 79:962-70
Dasinger, John Henry; Alexander, Barbara T (2016) Gender differences in developmental programming of cardiovascular diseases. Clin Sci (Lond) 130:337-48
Dasinger, John Henry; Davis, Gwendolyn K; Newsome, Ashley D et al. (2016) Developmental Programming of Hypertension: Physiological Mechanisms. Hypertension 68:826-31
Alexander, Barbara T; Dasinger, John Henry; Intapad, Suttira (2015) Fetal programming and cardiovascular pathology. Compr Physiol 5:997-1025
Intapad, Suttira; Ojeda, Norma B; Varney, Elliott et al. (2015) Sex-Specific Effect of Endothelin in the Blood Pressure Response to Acute Angiotensin II in Growth-Restricted Rats. Hypertension 66:1260-6
Alexander, Barbara T (2015) The Impact of Nutritional Insults during Fetal Life on Blood Pressure. J Nutr Sci Vitaminol (Tokyo) 61 Suppl:S5-6

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