Mechanisms of hypertension in women with polycystic ovary syndrome

Information

  • Research Project
  • 9995708
  • ApplicationId
    9995708
  • Core Project Number
    R01HL135089
  • Full Project Number
    3R01HL135089-02S1
  • Serial Number
    135089
  • FOA Number
    PA-16-160
  • Sub Project Id
  • Project Start Date
    1/1/2018 - 7 years ago
  • Project End Date
    11/30/2021 - 3 years ago
  • Program Officer Name
    MCDONALD, CHERYL
  • Budget Start Date
    9/15/2019 - 5 years ago
  • Budget End Date
    11/30/2019 - 5 years ago
  • Fiscal Year
    2019
  • Support Year
    02
  • Suffix
    S1
  • Award Notice Date
    9/9/2019 - 5 years ago

Mechanisms of hypertension in women with polycystic ovary syndrome

ABSTRACT Polycystic ovary syndrome (PCOS) is the most common reproductive endocrinopathy, affecting 1 in 10 reproductive age women. Approximately 75% of women with PCOS have the more severe reproductive and metabolic PCOS phenotype, which is dominated by features of hyperandrogenism, which include insulin resistance (IR), compensatory hyperinsulinemia, obesity, subcutaneous and visceral adiposity, dyslipidemia, as well as increased systolic and diastolic blood pressure and metabolic syndrome. In obese women with androgen excess (AE)-PCOS, peripheral vascular sympathetic nerve activity is increased. Importantly, free plasma testosterone level is a predictor of sympathetic nervous system (SNS)-mediated increases in blood pressure and renin angiotensin system (RAS) activation in women with AE-PCOS. With this application we propose novel Aims to discover the mechanisms for the androgen effects on the sympathetic contribution to blood pressure control in women with AE-PCOS and in our novel hyperandrogenemic female (HAF) rat model. Our overall hypothesis is that androgen excess in women with AE-PCOS leads to increased sympathetic activation that causes ?-adrenergic vasoconstriction and renal sympathetic nervous system activation to increase blood pressure. Androgen excess also increases angiotensinogen synthesis that would, in turn, stimulate RAS activity also increasing blood pressure. We will test these hypotheses in women with AE-PCOS and in a translational manner evaluate mechanisms in our HAF rat model. Aim 1 tests the hypothesis that the androgenic milieu is the primary driver for sympathetic activation associated with ?-adrenergic vasoconstriction, baroreflex sensitivity and increased blood pressure in AE-PCOS and in the HAF rats. Aim 2 tests the hypothesis that this androgen- driven sympathetic activation increases RAS activity and BP in AE-PCOS and the HAF rat. A most exciting, significant and novel aspect of this proposal is the compelling preliminary data demonstrating that increases in blood pressure are attenuated by ?1, ?1,2-adrenoceptor blockade and by renal denervation, which is consistent with our data showing testosterone suppression decreases blood pressure, and suppresses the RAS and the SNSA in women with AE-PCOS. With its focus on the integration of neural and renal control mechanisms of blood pressure in AE-PCOS, and its translational studies, concomitant with molecular investigations, this proposal is a departure from standard investigations of blood pressure regulation. Most importantly, should we demonstrate a relationship between androgens, SNSA and RAS, modulation of sympathetic activity could be a valuable treatment to inhibit the underlying causes of AE-PCOS.

IC Name
NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
  • Activity
    R01
  • Administering IC
    HL
  • Application Type
    3
  • Direct Cost Amount
    140000
  • Indirect Cost Amount
    114940
  • Total Cost
    254940
  • Sub Project Total Cost
  • ARRA Funded
    False
  • CFDA Code
    837
  • Ed Inst. Type
  • Funding ICs
    OD:254940\
  • Funding Mechanism
    Non-SBIR/STTR RPGs
  • Study Section
    ZRG1
  • Study Section Name
    Special Emphasis Panel
  • Organization Name
    JOHN B. PIERCE LABORATORY, INC.
  • Organization Department
  • Organization DUNS
    010139210
  • Organization City
    NEW HAVEN
  • Organization State
    CT
  • Organization Country
    UNITED STATES
  • Organization Zip Code
    065191403
  • Organization District
    UNITED STATES