; Female sex is the best established risk factor for pulmonary arterial hypertension (PAH), yet women have preserved right ventricular (RV) function and survival compared to men with PAH. This so-called """"""""estrogen paradox"""""""" is as yet unexplained. RV function determines outcome in disease, but the mechanisms and determinants of RV failure are unknown. We hypothesize that high estrogen states promote pulmonary vascular angiogenesis and RV myocardial collateral flow, resulting in pleiotropic effects on the pulmonary vasculature and the RV. In postmenopausal women, the hormonal mileu (e.g., sex hormone and estradiol [E2] metabolite levels) can be characterized;in premenopausal women the normal menstrual cycle (marked by a predictable spike in E2) provides a physiologic model to characterize these relationships. We propose: 1) a prospective cohort study (N=75) to determine whether the sex hormone milieu is associated with markers of angiogenesis (vascular endothelial growth factor [VEGF], angiopoietins [Ang], endothelial progenitor cells [EPCs]) and RV function assessed by hemodynamics in postmenopausal women wdth PAH and 2) a prospective case-control study (N = 40) to determine whether the menstrual cycle is associated with markers of angiogenesis (VEGF, Ang, EPCs) and RV function assessed by echocardiography in premenopausal women with PAH as compared to controls. We anticipate that in both pre and postmenopausal women, high E2 states will be associated with higher levels of angiogenesis markers but improved surrogates of RV function. The extent to which the influence of sex hormones on markers of angiogenesis and RV function can be defined is supported by 1) the use of separate studies to incorporate both pre and postmenopausal women and 2) the combination of a variety of carefully selected biomarkers aimed at both angiogenesis and RV function.

Public Health Relevance

Sex hormones are highly relevant targets for study, since RV function varies by sex and likely drives survival differences. If we find significant relationships between sex hormones and markers of angiogenesis/endothelial health, our next studies could focus on treatment or prevention strategies aimed at manipulation of E2 in those at risk for RV failure, a very innovative approach.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Exploratory Grants (P20)
Project #
1P20GM103652-01A1
Application #
8465684
Study Section
Special Emphasis Panel (ZGM1-TWD-B (CB))
Project Start
Project End
Budget Start
2013-09-20
Budget End
2014-05-31
Support Year
1
Fiscal Year
2013
Total Cost
$283,443
Indirect Cost
Name
Ocean State Research Institute, Inc.
Department
Type
DUNS #
848476271
City
Providence
State
RI
Country
United States
Zip Code
02908
Baird, Grayson L; Archer-Chicko, Christine; Barr, R Graham et al. (2018) Lower DHEA-S levels predict disease and worse outcomes in post-menopausal women with idiopathic, connective tissue disease- and congenital heart disease-associated pulmonary arterial hypertension. Eur Respir J 51:
Shah, Nishant R; Blankstein, Ron; Villines, Todd et al. (2018) Coronary CTA for Surveillance of Cardiac Allograft Vasculopathy. Curr Cardiovasc Imaging Rep 11:26
Monaghan, Sean F; Banerjee, Debasree; Chung, Chun-Shiang et al. (2018) Changes in the process of alternative RNA splicing results in soluble B and T lymphocyte attenuator with biological and clinical implications in critical illness. Mol Med 24:32
Potz, Brittany A; Scrimgeour, Laura A; Pavlov, Vasile I et al. (2018) Extracellular Vesicle Injection Improves Myocardial Function and Increases Angiogenesis in a Swine Model of Chronic Ischemia. J Am Heart Assoc 7:
Zhou, Yang; He, Chuan Hua; Yang, Daniel S et al. (2018) Galectin-3 Interacts with the CHI3L1 Axis and Contributes to Hermansky-Pudlak Syndrome Lung Disease. J Immunol 200:2140-2153
Zhao, Haifeng; Dennery, Phyllis A; Yao, Hongwei (2018) Metabolic reprogramming in the pathogenesis of chronic lung diseases, including BPD, COPD, and pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 314:L544-L554
Chambers, Eboni; Rounds, Sharon; Lu, Qing (2018) Pulmonary Endothelial Cell Apoptosis in Emphysema and Acute Lung Injury. Adv Anat Embryol Cell Biol 228:63-86
Sellke, Nicholas; Kuczmarski, Alex; Lawandy, Isabella et al. (2018) Enhanced coronary arteriolar contraction to vasopressin in patients with diabetes after cardiac surgery. J Thorac Cardiovasc Surg 156:2098-2107
Fallon, Eleanor A; Biron-Girard, Bethany M; Chung, Chun-Shiang et al. (2018) A novel role for coinhibitory receptors/checkpoint proteins in the immunopathology of sepsis. J Leukoc Biol :
Aldosari, Sarah; Awad, Maan; Harrington, Elizabeth O et al. (2018) Subcellular Reactive Oxygen Species (ROS) in Cardiovascular Pathophysiology. Antioxidants (Basel) 7:

Showing the most recent 10 out of 96 publications