Estrogen receptor-alpha effects on right ventricular vascular density and angiogenesis in pulmonary hypertension

雌激素受体-α 对肺动脉高压右心室血管密度和血管生成的影响

• 批准号: 10556350
• 负责人: Tim Lahm
• 金额: --
• 依托单位: VA EASTERN COLORADO HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10556350
• 关键词: APLN gene; Activities of Daily Living; Address; Agonist; Animals; Anti-Inflammatory Agents; Apoptosis; Apoptotic; Area; Attenuated; Autophagocytosis; Award; Biological Assay; Biology; Blood Vessels; Blood capillaries; Cardiac; Cardiac development; Cell Survival; Cell physiology; Cessation of life; Chronic Obstructive Pulmonary Disease; Complement; Complication; Data; Development; Disease; Dissection; Echocardiography; Endothelial Cells; Estradiol; Estrogen Receptor alpha; Exhibits; Female; Functional disorder; Funding; Goals; Gonadal Steroid Hormones; Health; Heart; Heart Diseases; Impairment; Knock-out; Knowledge; Lectin; Left; Link; Longevity; Lung; Measures; Mediating; Mediator of activation protein; Mission; Mitochondria; Modeling; Molecular; Mus; Pathway interactions; Patients; Play; Publishing; Pulmonary Fibrosis; Pulmonary Heart Disease; Pulmonary Hypertension; Pulmonary artery structure; Quality of life; Rattus; Regulation; Research; Right Ventricular Dysfunction; Right Ventricular Function; Right Ventricular Hypertrophy; Rodent; Role; Running; Signal Pathway; Signal Transduction; Sleep Apnea Syndromes; Stains; Structure; Therapeutic; Time; Tissues; Tube; Up-Regulation; VO2max; Ventricular; Veterans; Work; angiogenesis; base; bone morphogenetic protein receptors; density; exercise capacity; experimental study; heart function; hormonal signals; improved; in vivo; innovation; loss of function; male; matrigel; migration; new therapeutic target; novel; premature; pressure; prognostic; protective effect; pulmonary vascular remodeling; receptor; response; right ventricular failure; right ventricular remodeling; sex; tool; treadmill

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 17β-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 ERα, and suggest a new mechanism by which ERα 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 ERα- 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 ERα to increasing capillary density in the RV. We generated a novel ERα knockout rat that will enable us to study the role of ERα 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 ERα 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 ERα as a critical modulator of RV function and 2) establish a novel and therapeutically targetable E2-ERα- 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 ERα knockout rat model, through use of a new highly selective ERα agonist that will allow for mechanistic dissection of ERα’s role in ECs from failing RVs, and through use of unbiased stereology. Upon completion of the proposed studies, we will have identified ERα 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.

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 17β-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 ERα, and suggest a new mechanism by which ERα 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 ERα- 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 ERα to increasing capillary density in the RV. We generated a novel ERα knockout rat that will enable us to study the role of ERα 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 ERα 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 ERα as a critical modulator of RV function and 2) establish a novel and therapeutically targetable E2-ERα- 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 ERα knockout rat model, through use of a new highly selective ERα agonist that will allow for mechanistic dissection of ERα’s role in ECs from failing RVs, and through use of unbiased stereology. Upon completion of the proposed studies, we will have identified ERα 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.

项目成果

Taking it to heart: dissecting cardiopulmonary interactions in diseases of the lung and the cardiovascular system.

牢记于心：剖析肺部和心血管系统疾病中的心肺相互作用。

• DOI: 10.1152/ajplung.00373.2020
• 发表时间: 2020
• 期刊: American journal of physiology. Lung cellular and molecular physiology
• 作者: Lahm,Tim

Tips for success in pulmonary hypertension treatment: progress in isolating endothelial cells from pulmonary artery catheters.

肺动脉高压治疗成功的秘诀：从肺动脉导管中分离内皮细胞的进展。

• DOI: 10.1183/13993003.00122-2020
• 发表时间: 2020
• 期刊: The European respiratory journal
• 作者: Frump,AndreaL;Lahm,Tim
• 通讯作者: Lahm,Tim

Metabolite G-Protein Coupled Receptors in Cardio-Metabolic Diseases.

• DOI: 10.3390/cells10123347
• 发表时间: 2021-11-29
• 期刊: Cells
• 影响因子: 6
• 作者: Strassheim D;Sullivan T;Irwin DC;Gerasimovskaya E;Lahm T;Klemm DJ;Dempsey EC;Stenmark KR;Karoor V
• 通讯作者: Karoor V

Hormones, Hemodynamics, and Hepatic Function: Digesting the Intricacies of Sex Differences in Portopulmonary Hypertension.

激素、血流动力学和肝功能：消化门脉肺动脉高压性别差异的复杂性。

• DOI: 10.1016/j.chest.2020.09.240
• 发表时间: 2021
• 期刊: Chest
• 影响因子: 9.6
• 作者: Lahm,Tim

Estrogen administered after cardiac arrest and cardiopulmonary resuscitation ameliorates acute kidney injury in a sex- and age-specific manner.

• DOI: 10.1186/s13054-015-1049-8
• 发表时间: 2015-09-18
• 期刊: Critical care (London, England)
• 作者: Ikeda M;Swide T;Vayl A;Lahm T;Anderson S;Hutchens MP
• 通讯作者: Hutchens MP