Adverse intrauterine environment during the critical period of fetal development predisposes organisms to increased risk for developing hypertension. We and others using a low-protein (LP) model of fetal programming demonstrated that hypertension in offspring is gender related, with a greater effect in males than females, and endocrine changes may underlie the development of hypertension. The central hypothesis is that sex steroid hormones, testosterone (T) and estradiol (E2), via interaction with a variety of regulatory path- ways, regulate the development and progression of maternal LP-induced hypertension in the offspring. Effects include changes in vascular steroid receptors, endothelial and smooth muscle (VSM) function, and vascular rennin angiotensin system (RAS).
Three specific aims are proposed.
Specific Aim 1 : Investigate the influence of sex steroids on maternal LP-induced developmental origins of hypertension in male and female offspring.
Specific Aim 1 a. Is the onset and severity of hypertension related to changes in sex steroids? We hypothesize that endocrine dysfunction will precede the development of hypertension with a more pronounced effect in males than females.
Specific Aim 1 b. Are alterations in blood pressure (BP) in the offspring specific to changes in the levels of sex steroids? We hypothesize that OVX in females exacerbates, while OCX in males dampens, the onset and severity of hypertension, and these changes are reversed by respective steroid replacement and flutamide. Growth rate, adiposity, and changes in MAP and plasma T and E2 will be assessed.
Specific Aim 2 : Characterization of endothelial and VSM cell functions and their regulation by sex steroids in hypertensive offspring. We hypothesize that endocrine dysfunction will alter expression of steroid receptors, endothelial, and VSM functions in LP offspring, and these effects are hormone specific.
Specific Aim 2 a. Are alterations in BP in the offspring specific to changes in the levels of sex steroid receptors? Specific Aim 2b. Is endothelial cell function altered and related to changes in T and E2 levels in hypertensive offspring? Specific Aim 2c. Is VSM cell function altered and related to changes in T and E2 levels in hypertensive offspring? Specific Aim 2d. Are alterations in the function of endothelium and VSM specific to changes in T and E2 levels in hypertensive offspring? Specific Aim 3: Characterization of vascular RAS function and regulation by sex steroids in hypertensive offspring. We hypothesize that alteration in T and E2 levels will alter expression and activity of RAS components, and thus BP, in LP offspring.
Specific Aim 3 a. Is the function and expression of RAS components altered with age and related to changes in T and E2 levels in the hypertensive offspring? Specific Aim 3b. Are the expression and activity of RAS components in hyper- tensive offspring specific to changes in T and E2 using gonadectomy in LP offspring? The study will assess if these changes are reversed with respective hormones and flutamide. Collectively, these studies will yield important insights that could aid in developing sex-specific strategies for preventing and treating hypertension.

Public Health Relevance

Programming of adult health and disease appears to be dependent upon fetal exposure to various in utero environmental factors. Many models of fetal programming and epidemiological data in humans suggest gender-dependent variation in the susceptibility to hypertension. This proposal will yield important insights that could aid in the development of sex-specific strategies for the prevention and treatment of hypertension.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL102866-03
Application #
8383460
Study Section
Special Emphasis Panel (ZRG1-EMNR-P (02))
Program Officer
Pemberton, Victoria
Project Start
2010-12-01
Project End
2013-08-31
Budget Start
2012-12-01
Budget End
2013-08-31
Support Year
3
Fiscal Year
2013
Total Cost
$364,140
Indirect Cost
$126,140
Name
University of Texas Medical Br Galveston
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555
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Blesson, Chellakkan S; Sathishkumar, Kunju; Chinnathambi, Vijayakumar et al. (2014) Gestational protein restriction impairs insulin-regulated glucose transport mechanisms in gastrocnemius muscles of adult male offspring. Endocrinology 155:3036-46
Chinnathambi, Vijayakumar; Blesson, Chellakkan S; Vincent, Kathleen L et al. (2014) Elevated testosterone levels during rat pregnancy cause hypersensitivity to angiotensin II and attenuation of endothelium-dependent vasodilation in uterine arteries. Hypertension 64:405-14
Chinnathambi, Vijayakumar; More, Amar S; Hankins, Gary D et al. (2014) Gestational exposure to elevated testosterone levels induces hypertension via heightened vascular angiotensin II type 1 receptor signaling in rats. Biol Reprod 91:6
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Gao, Haijun; Yallampalli, Uma; Yallampalli, Chandra (2013) Gestational protein restriction affects trophoblast differentiation. Front Biosci (Elite Ed) 5:591-601
Chinnathambi, Vijayakumar; Balakrishnan, Meena; Ramadoss, Jayanth et al. (2013) Testosterone alters maternal vascular adaptations: role of the endothelial NO system. Hypertension 61:647-54
Havemann, Dara; Balakrishnan, Meena; Borahay, Mostafa et al. (2013) Intermedin/adrenomedullin 2 is associated with implantation and placentation via trophoblast invasion in human pregnancy. J Clin Endocrinol Metab 98:695-703
Chinnathambi, Vijayakumar; Yallampalli, Chandrasekhar; Sathishkumar, Kunju (2013) Prenatal testosterone induces sex-specific dysfunction in endothelium-dependent relaxation pathways in adult male and female rats. Biol Reprod 89:97

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