Epidemiological studies show increased risk of cardiovascular (CV) diseases in children born to women with compromised pregnancies, such as in preeclampsia, PCOS, protein or energy restriction, obesity, stress, and smoking, but its pathogenesis remains incompletely understood. As one of the common factors observed in these pregnancy pathologies, elevated maternal testosterone (T) is likely to contribute to the fetal programming of CV disorders. Indeed, our recent studies demonstrate that elevated maternal T causes development of hypertensive phenotypes in rat offspring. To understand the mechanisms, 2 central hypotheses are proposed in this project. First, prenatal T induces sex-specific onset and severity of hypertension, and these hypertensive responses are mediated by postnatal increases in T levels. Second, increase in postnatal T induces hypertensive responses through sex-specific dysfunctions in vascular smooth muscle (VSM) protein kinase C (PKC) and endothelial EDHF/NO expression/function. To test these hypotheses, we propose a series of experiments in our established pregnant rat model and examine their offspring.
Three specific aims are proposed: 1) Determine whether elevated maternal T programs offspring's hypertension, with more pronounced effect in males than females, and if postnatal T increase precedes hypertension onset. We will telemetrically monitor progressive changes in blood pressure (BP) and measure T levels to establish a relationship between onset and severity of hypertension and changes in postnatal T levels, mechanistically determining if postnatal T increase is the key contributing factor for BP increase. 2) Evaluate the sex-specific hypertensive mechanisms in VSM. We will examine the PKC isoenzyme expression profile in subcellular fractions, its phosphorylation status, and functional activity and examine mechanisms by which androgens regulate PKC expression by assessing binding of T to putative ARE in PKC promoter by ChiP and reporter assays. 3) Dissect the sex-specific mechanisms of impaired endothelial functions. We will examine the EDHF- and NO-mediated pathways and evaluate the mechanisms for impaired EDHF-mediated vasodilation by determining mRNA and protein levels of EDHF components SK3 and IK1 channels and connexins (CX37, CX40, and CX47), their subcellular localization, and functional activity using vascular reactivity and membrane potential studies. We will investigate the role of impaired NO-mediated vasodilator function by assessing the expression of eNOS, its activity, NO production, and signaling events. We expect that in utero T exposure will cause gender-specific hypertensive effects through upregulation of distinct vascular PKC isoenzymes and differential endothelial dysfunctions in the male and female vasculature, which may be regulated through postnatal changes in T levels. The results will provide a novel molecular basis to the understanding of fetal programming of adult CV dysfunction and improve our knowledge of sex differences in vascular dysfunction, providing an exciting opportunity to devise sex-specific strategies for prevention and treatment of hypertension.

Public Health Relevance

Cardiovascular disease is the #1 killer worldwide. The proposed studies, focusing on a molecular mechanistic link between adverse intrauterine environments and development of a hypertensive phenotype, will provide direct evidence that elevated androgen levels during pregnancy increase the risk of hypertension and cardiovascular disease in the offspring. This new evidence will provide several possible approaches to improving vascular function and reducing high blood pressure in the clinical setting.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Pregnancy and Neonatology Study Section (PN)
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Mitchell, Megan S
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University of Texas Medical Br Galveston
Obstetrics & Gynecology
Schools of Medicine
United States
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Blesson, Chellakkan S; Chinnathambi, Vijayakumar; Kumar, Sathish et al. (2017) Gestational Protein Restriction Impairs Glucose Disposal in the Gastrocnemius Muscles of Female Rats. Endocrinology 158:756-767
Mishra, Jay S; More, Amar S; Hankins, Gary D V et al. (2017) Hyperandrogenemia reduces endothelium-derived hyperpolarizing factor-mediated relaxation in mesenteric artery of female rats. Biol Reprod 96:1221-1230
Sheibani, Lili; Lechuga, Thomas J; Zhang, Honghai et al. (2017) Augmented H2S production via cystathionine-beta-synthase upregulation plays a role in pregnancy-associated uterine vasodilation. Biol Reprod 96:664-672
Gopalakrishnan, Kathirvel; Mishra, Jay S; Chinnathambi, Vijayakumar et al. (2016) Elevated Testosterone Reduces Uterine Blood Flow, Spiral Artery Elongation, and Placental Oxygenation in Pregnant Rats. Hypertension 67:630-9
Mishra, Jay S; Hankins, Gary D; Kumar, Sathish (2016) Testosterone downregulates angiotensin II type-2 receptor via androgen receptor-mediated ERK1/2 MAP kinase pathway in rat aorta. J Renin Angiotensin Aldosterone Syst 17:
More, Amar S; Mishra, Jay S; Hankins, Gary D et al. (2016) Prenatal Testosterone Exposure Decreases Aldosterone Production but Maintains Normal Plasma Volume and Increases Blood Pressure in Adult Female Rats. Biol Reprod 95:42
More, Amar S; Mishra, Jay S; Gopalakrishnan, Kathirvel et al. (2016) Prenatal Testosterone Exposure Leads to Gonadal Hormone-Dependent Hyperinsulinemia and Gonadal Hormone-Independent Glucose Intolerance in Adult Male Rat Offspring. Biol Reprod 94:5
Gopalakrishnan, Kathirvel; More, Amar S; Hankins, Gary D et al. (2016) Postnatal Cardiovascular Consequences in the Offspring of Pregnant Rats Exposed to Smoking and Smoking Cessation Pharmacotherapies. Reprod Sci :
Blesson, Chellakkan S; Chinnathambi, Vijayakumar; Hankins, Gary D et al. (2015) Prenatal testosterone exposure induces hypertension in adult females via androgen receptor-dependent protein kinase C?-mediated mechanism. Hypertension 65:683-690
Sathishkumar, Kunju; Balakrishnan, Meena P; Yallampalli, Chandrasekhar (2015) Enhanced mesenteric arterial responsiveness to angiotensin II is androgen receptor-dependent in prenatally protein-restricted adult female rat offspring. Biol Reprod 92:55

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