Hypoxia-induced pulmonary hypertension (HPH) is a serious clinical problem in veterans with chronic lung disease. 17beta-estradiol (E2) attenuates HPH, but the mechanisms are poorly understood. Our preliminary data demonstrate that 1) E2's anti-proliferative effects occur exclusively during actual or chemical hypoxia and 2) hypoxia upregulates estrogen receptor (ER) transcription and/or expression in pulmonary artery endothelial cells (PAECs) and the right ventricle (RV). We hypothesize that the mechanism through which E2 attenuates PH development and improves RV function is through hypoxia- and hypoxia-inducible factor (HIF) 1alpha- enabled increases in ER expression in the PA-RV unit, with subsequent induction of cellular autophagy and improved RV mitochondrial biogenesis. Since RV failure in both HPH as well as non-hypoxic forms of PH is characterized by global or local (cellular) hypoxia with activation of known HIF-1alpha inducers, we propose that the RV-protective effects of the E2-ER-axis against hypoxia-induced (adaptive) RV remodeling will extend to RV failure characterized by maladaptive remodeling. Our mechanistic experimental approach utilizes comprehensive clinically relevant PH endpoints in vivo, complemented by studies in primary PAECs. We propose the following specific aims: SA#1: To determine if enhancing ER signaling protects against development of PH. 1a: To establish the pattern and time course of hypoxia- and HIF1?-induced increases in ER expression in the pulmonary vasculature and RV. 1b: To investigate if transgenic conditional tissue-specific enhancement of ER signaling potentiates E2's protective effects in HPH and even in non-hypoxic forms of PH. 1c: To interrogate whether enhancing ER signaling is sufficient to protect against HPH or non-hypoxic PH even in the absence of further stimulation by exogenous E2 SA#2: To establish the mechanisms by which E2 inhibits RV remodeling and improves RV function during both adaptive and maladaptive RV responses in PH. 2a: To elucidate if E2 protects against pathological RV remodeling by a mechanism involving ER?-dependent autophagy in both adaptive and maladaptive RV hypertrophy models. 2b: To investigate if E2 improves RV function by optimizing mitochondrial substrate utilization during both adaptive and maladaptive RV responses in PH. In vivo experiments will be performed in two distinct rodent models of PH: a) HPH and b) VEGF-receptor blockade plus hypoxia-induced PH. We will primarily employ transgenic mouse models for mechanistic experiments, and use rats for studies requiring comprehensive analysis of functional endpoints. Endpoints assessed in vivo include hemodynamics, RV form/function by echocardiography, exercise capacity, and PA/RV remodeling, complemented by in vivo and in vitro measurements of ER expression, cellular proliferation, survival, apoptosis and autophagy, as well as HIF-1alpha activation and mitochondrial substrate utilization. The proposed studies are novel because they will 1) for the first time establish the mechanisms of ER protection in the cardiopulmonary system;2) be the first investigations to extend the protective effects of E2 to more severe forms of RV failure;and 3) substantiate the novel appreciation of the key role of autophagy and mitochondrial substrate utilization in ER-mediated protection in the failing RV. The studies proposed are significant because 1) the results will facilitate the identification of new therapeutic targets directed at advanced forms of RV failure; 2) the work will be a critical step towards our long-term goal of developing targeted non-hormonal therapies to benefit male and female veterans with PH;and 3) the results may explain why women are more prone to idiopathic pulmonary arterial hypertension development, yet - once affected - exhibit less severe disease.

Public Health Relevance

The proposed research will allow us to better define the functional consequences of increased estrogen receptor expression and signaling in hypoxia-induced pulmonary hypertension and right ventricular failure. This will provide the rationale and basis for identifying novel mechanisms of action of estrogens in the cardiopulmonary axis, and for developing targeted, non-hormonal treatment strategies for patients with pulmonary vascular and/or right ventricular disease. The proposed research is relevant to the mission of this RFA, because it will identify novel biological effectors of estrogen signaling, characterize novel intracellular signaling events and implicate autophagy and mitochondrial substrate utilization as previously unappreciated molecular targets of estrogens in the cardiopulmonary unit. Insights gained from our research may therefore help improve the health and longevity of veterans with chronic lung disease.

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Veterans Affairs (VA)
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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
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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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