Pulmonary hypertension (PH) and right ventricular (RV) dysfunction are extremely common in veterans. Up to 80% of veterans with chronic obstructive pulmonary disease, pulmonary fibrosis, sleep disordered breathing or LV dysfunction (either systolic or diastolic) suffer from PH. Better RV function and female sex have been linked to improved survival in PH, and female patients exhibit better RV function than their male counterparts. This proposal builds on the scientific premise that even though RV function and female sex are major determinants of survival in PH, no RV-specific or sex steroid-directed therapies exist. Endothelial cell (EC) dysfunction and impaired angiogenesis play a major role in the development of RV failure, and data obtained in the previous funding period demonstrate that the female sex steroid 17?-estradiol (E2) increases capillary density in the RV and stimulates angiogenesis in cultured cardiac ECs. The goal of this proposal is to identify novel and therapeutically targetable mechanisms by which E2 exerts protective effects on RV EC function in PH. We provide evidence that E2 exerts its RV EC-protective effects via its receptor ER?, and suggest a new mechanism by which ER? activates bone morphogenetic protein receptor 2 (BMPR2) signaling to upregulate apelin, a potent angiogenesis mediator and EC survival factor, whose regulation in the RV is not yet known. Based on these findings, we now put forward the novel hypothesis that E2 improves RV function in PH by ER?- and BMPR2-dependent up-regulation of EC apelin. We propose the following specific aims: 1) To establish that E2 increases capillary density in the RV via BMPR2-dependent increases in EC apelin, and 2) To identify the contribution of ER? to increasing capillary density in the RV. We generated a novel ER? knockout rat that will enable us to study the role of ER? in the rat pulmonary artery banding model, thus avoiding the pitfalls of prior studies of sex hormone signaling performed in PH models without RV failure. These studies will be complemented by studies of BMPR2-deficient rats and apelin-deficient mice. These loss- of-function studies will be accompanied by studies in which we interrogate the therapeutic potential of ER? agonists, BMPR2 activators and apelin receptor agonists. We will complement these in vivo studies with experiments in RV ECs isolated from rodents with RV failure and from patients with compensated (adaptive) or decompensated (maladaptive) RV hypertrophy. Endpoints investigated will include RV function and structure (by pressure volume loops and echocardiography), exercise capacity (measured as VO2 max via treadmill running), RV capillary density (quantified using unbiased stereology and lectin staining), angiogenesis assays (matrigel tube formation and transwell migration), BMPR2 and apelin signaling pathways, as well as mediators of angiogenesis and EC survival and apoptosis. The proposed studies are significant, since they will 1) identify ER? as a critical modulator of RV function and 2) establish a novel and therapeutically targetable E2-ER?- BMPR2-apelin axis in RV ECs. The proposed studies are innovative, since they, for the first time, will provide a molecular basis for E2's RV- and EC-protective effects in PH. In addition, they provide technical innovation through use of a newly generated ER? knockout rat model, through use of a new highly selective ER? agonist that will allow for mechanistic dissection of ER??s role in ECs from failing RVs, and through use of unbiased stereology. Upon completion of the proposed studies, we will have identified ER? as a novel mediator of adaptive signaling in RV ECs. This may ultimately allow for the development of new RV-directed, non- hormonal treatments for both female and male veterans with PH and RV failure.

Public Health Relevance

The proposed research is relevant to the health of veterans because it will determine the underlying mechanisms of how the sex hormone 17?-estradiol improves right heart function in pulmonary hypertension, a progressive cardiopulmonary disease that is caused by thickening of the blood vessels of the lung and that leads to premature death from right heart failure. Even though pulmonary hypertension and right heart failure complicate many diseases that frequently occur in veterans (e.g. chronic obstructive pulmonary disease, pulmonary fibrosis, sleep disordered breathing and left heart disease), no cure for pulmonary hypertension is available, and no specific therapies for the failing right heart exist. The proposed work is relevant to the mission of the VA, since it will lead to the development of novel treatments for both male and female veterans with right heart failure from pulmonary hypertension or other cardiopulmonary diseases.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Cardiovascular Studies A (CARA)
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Rlr VA Medical Center
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Lahm, Tim; Douglas, Ivor S; Archer, Stephen L et al. (2018) Assessment of Right Ventricular Function in the Research Setting: Knowledge Gaps and Pathways Forward. An Official American Thoracic Society Research Statement. Am J Respir Crit Care Med 198:e15-e43
Leary, Peter J; Maron, Bradley A; Tedford, Ryan J et al. (2018) Pulmonary Hypertension: Good Intentions, But a Questionable Approach. Ann Am Thorac Soc 15:664-666
Elinoff, Jason M; Agarwal, Richa; Barnett, Christopher F et al. (2018) Challenges in Pulmonary Hypertension: Controversies in Treating the Tip of the Iceberg. A Joint National Institutes of Health Clinical Center and Pulmonary Hypertension Association Symposium Report. Am J Respir Crit Care Med 198:166-174
Frump, Andrea L; Bonnet, S├ębastien; de Jesus Perez, Vinicio A et al. (2018) Emerging role of angiogenesis in adaptive and maladaptive right ventricular remodeling in pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 314:L443-L460
Han, MeiLan K; Arteaga-Solis, Emilio; Blenis, John et al. (2018) Female Sex and Gender in Lung/Sleep Health and Disease. Increased Understanding of Basic Biological, Pathophysiological, and Behavioral Mechanisms Leading to Better Health for Female Patients with Lung Disease. Am J Respir Crit Care Med 198:850-858
Vieillard-Baron, Antoine; Naeije, R; Haddad, F et al. (2018) Diagnostic workup, etiologies and management of acute right ventricle failure : A state-of-the-art paper. Intensive Care Med :
Frump, Andrea L; Lahm, Tim (2018) The Y Chromosome Takes the Field to Modify BMPR2 Expression. Am J Respir Crit Care Med 198:1476-1478
Frump, Andrea L; Selej, Mona; Wood, Jordan A et al. (2018) Hypoxia Upregulates Estrogen Receptor ? in Pulmonary Artery Endothelial Cells in a HIF-1?-Dependent Manner. Am J Respir Cell Mol Biol 59:114-126
Brown, Mary Beth; Neves, Evandro; Long, Gary et al. (2017) High-intensity interval training, but not continuous training, reverses right ventricular hypertrophy and dysfunction in a rat model of pulmonary hypertension. Am J Physiol Regul Integr Comp Physiol 312:R197-R210
Lahm, Tim; Frump, Andrea L (2017) Toward Harnessing Sex Steroid Signaling as a Therapeutic Target in Pulmonary Arterial Hypertension. Am J Respir Crit Care Med 195:284-286

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