Sex-specific fetal programming of adult vascular dysfunction and hypertension

Summary

Principal Investigator: KUNJU REDDIAR SATHISH KUMAR
Abstract: DESCRIPTION (provided by applicant): 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.
Funding Period: 2013-08-09 - 2018-05-31
more information: NIH RePORT

Top Publications

  1. pmc Prenatal testosterone induces sex-specific dysfunction in endothelium-dependent relaxation pathways in adult male and female rats
    Vijayakumar Chinnathambi
    Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, Texas
    Biol Reprod 89:97. 2013
  2. pmc Elevated testosterone levels during rat pregnancy cause hypersensitivity to angiotensin II and attenuation of endothelium-dependent vasodilation in uterine arteries
    Vijayakumar Chinnathambi
    From the Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston V C, K L V, G R S, G D H, K S and Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX C S B, C Y
    Hypertension 64:405-14. 2014

Detail Information

Publications2

  1. pmc Prenatal testosterone induces sex-specific dysfunction in endothelium-dependent relaxation pathways in adult male and female rats
    Vijayakumar Chinnathambi
    Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, Texas
    Biol Reprod 89:97. 2013
    ....
  2. pmc Elevated testosterone levels during rat pregnancy cause hypersensitivity to angiotensin II and attenuation of endothelium-dependent vasodilation in uterine arteries
    Vijayakumar Chinnathambi
    From the Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston V C, K L V, G R S, G D H, K S and Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX C S B, C Y
    Hypertension 64:405-14. 2014
    ..These results suggest that elevated maternal testosterone impairs uterine vascular function, which may lead to an increased vascular resistance and a decrease in uterine blood flow. ..

Research Grants30

  1. Developmental programming: influence of sex steroids and mechanisms
    Chandrasekhar Yallampalli; Fiscal Year: 2013
    ..Collectively, these studies will yield important insights that could aid in developing sex-specific strategies for preventing and treating hypertension. ..
  2. Acute and Chronic Afferent Engagement: Sympathetic and End Organ Responses
    Lawrence I Sinoway; Fiscal Year: 2013
    ..Two cores are proposed: 1) Core A will be administrative;and 2) Core B will be a human physiology core. ..
  3. Vascular Mechanisms in Pregnancy-Induced Hypertension
    Raouf A Khalil; Fiscal Year: 2013
    ....
  4. Vascular Interactions of Estrogen Receptor GPR30 and the Renin-Angiotensin System
    Sarah Hoffmann Lindsey; Fiscal Year: 2013
    ..These studies will establish the regulation of'Vascular GPR30 expression and assess its acute and chronic interaction with the renin-angiotensin system. ..
  5. Lentiviral Gene Therapy for Sickle Cell Disease and Immunodeficiency Disorders
    Brian P Sorrentino; Fiscal Year: 2013
    ..abstract_text> ..
  6. Translating molecular signal pathways to orthopaedic trauma care
    REGIS J O'KEEFE; Fiscal Year: 2013
    ..abstract_text> ..
  7. Prenatal Events-Postnatal Consequences
    James C Rose; Fiscal Year: 2013
    ..Therefore our work may promote the identification of new, early intervention strategies to reduce the risk of hypertension as well as renal and metabolic abnormalities in antenatal steroid exposed individuals. ..
  8. Mechanisms of Risk and Resilience in ASD: Ontogeny, Phylogeny and Gene Disruption
    Ami Klin; Fiscal Year: 2013
    ..abstract_text> ..
  9. Importance of Endothelial Cell-Cell Communication at the Maternal Fetal Interface
    Ronald R Magness; Fiscal Year: 2013
    ..This leads to indepth understanding of the inter/intracellular mechanisms at the maternal-fetal interface in normal and abnormal pregnancies (e.g. preeclampsia with lUGR). ..
  10. Birth, Muscle Injury and Pelvic Floor Dysfunction
    John O L Delancey; Fiscal Year: 2013
    ..It will establish the scientific basis for new strategies to improve treatment, identify important prevention opportunities, and train a new generation of researchers. ..
  11. FOREBRAIN PLASTICY IN HYPERTENSION
    Costantino Iadecola; Fiscal Year: 2013
    ..Thus, the collective scientific outcome of the Program is anticipated to be greater than the sum of its individual components. ..
  12. RGS Protein Function and Regulation
    Kendall J Blumer; Fiscal Year: 2013
    ..Accordingly, this project advances understanding of blood pressure control mechanisms and their dysregulation in hypertension, which may contribute to the identification of new hypertension therapies. ..
  13. CARDIOVASCULAR DYNAMICS AND THEIR CONTROL
    John E Hall; Fiscal Year: 2013
    ..End of Abstract) ..
  14. Mechanisms of Health Effects of Exercise in Children
    Dan M Cooper; Fiscal Year: 2013
    ..Collectively, the PPG will promote novel preventive and adjunctive exercise therapies in children with chronic inflammation- therapies grounded in a firm understanding of biological mechanisms. ..
  15. Immune-Based Interventions Against Infectious Diseases
    Alan L Rothman; Fiscal Year: 2013
    ..3. Recruit promising junior investigators and provide mentoring by established NIH-funded researchers. 4. Support a multidisciplinary research program led by junior investigators in translational infectious diseases immunology. ..
  16. Lactation Effects on Postnatal Endothelial Function and Vascular Inflammation
    Karen M Grewen; Fiscal Year: 2013
    ..The proposed research is significant because it is expected to advance understanding of early mechanisms of CVD, the #1 cause of death for women in the U.S, and has potential for widespread positive impact on women's health. ..
  17. MITOCHONDRIAL ENCEPHALOMYOPATHIES AND MENTAL RETARDATION
    Salvatore DiMauro; Fiscal Year: 2013
    ....
  18. Stanford University Center for Reproductive and Stem Cell biology
    Margaret T Fuller; Fiscal Year: 2013
    ..abstract_text> ..
  19. HORMONAL REGULATION OF BLOOD PRESSURE
    Michal Laniado Schwartzman; Fiscal Year: 2013
    ..ular tone, in the pathophysiology of hypertension and cardiovascular disease. ..
  20. Elucidating Risks: From Exposure and Mechanism to Outcome
    James A Swenberg; Fiscal Year: 2013
    ..This Program is highly relevant to Superfund by addressing high-priority chemicals and by focusing on mechanisms underlying health effects, exposure assessment, and remediation to mitigate exposure and toxicity. ..
  21. Neurohumoral control of veins in hypertension
    Gregory D Fink; Fiscal Year: 2013
    ..This project tests the idea that altered structure or function of veins also may cause hypertension, and that it may be possible to treat hypertension using drugs that affect veins. ..
  22. Mechanisms of Microvascular Control and Coordination in Health and Disease
    Gerald A Meininger; Fiscal Year: 2013
    ..End of Abstract) ..
  23. ENDOTHELIN CONTROL OF RENAL HEMODYNAMIC AND EXCRETORY FUNCTION
    David M Pollock; Fiscal Year: 2013
    ..In particular, this Program will investigate a full range of mechanisms that control ET-1 release and receptor specific actions in order to provide clinically relevant information. ..
  24. Regulatory Mechanisms In Intestinal Motility
    Kenton M Sanders; Fiscal Year: 2013
    ..The investigative team is highly synergistic and collaborative, and the PPG has a long track-record of productivity and novel discovery ..