Nicholas T. Severyn, Patricia Esparza, Huanling Gao, Elizabeth A. Mickler, Marjorie E. Albrecht, Amanda Fisher, Bakhtiyor Yakubov, Todd G. Cook, James E. Slaven, Avram D. Walts, Robert S. Tepper, Tim Lahm
University of Kentucky. Indiana University – Purdue University Indianapolis. University of Colorado. National Jewish Health.
United States
American Journal of Physiology Lung Cellular and Respiratory Physiology
Am J Phyiol Lung Cell Mol Physiol 2024;
DOI: 10.1152/ajplung.00161.2023
Abstract
Humans living at high-altitude (HA) have adapted to this environment by increasing pulmonary vascular and alveolar growth. RNA sequencing data from a novel murine model that mimics this phenotypical response to HA suggested estrogen signaling via estrogen receptor alpha (ERα) may be involved in this adaptation. We hypothesized ERα was a key mediator in the cardiopulmonary adaption to chronic hypoxia and sought to delineate the mechanistic role ERα contributes to this process by exposing novel loss-of-function ERα mutant (ERαMut) rats to simulated HA. ERα mutant or wild type (wt) rats were exposed to normoxia or hypoxia starting at conception and continued postnatally until 6 weeks of age. Both wt and ERαMut animals born and raised in hypoxia exhibited lower body mass and higher hematocrits, total alveolar volumes (Va), diffusion capacities of carbon monoxide (DLCO), pulmonary arteriole (PA) wall thickness, and Fulton indices than normoxia animals. Right ventricle adaptation was maintained in the setting of hypoxia. While no major physiologic differences were seen between wt and ERαMut animals at either exposure, ERαMut animals exhibited smaller mean linear intercepts (MLI) and increased PA total and lumen areas. Hypoxia exposure or ERα loss-of-function did not affect lung mRNA abundance of vascular endothelial growth factor, angiopoietin 2 or apelin. Sexual dimorphisms were noted in PA wall thickness and lumen area in ERαMut rats. In summary, in room air-exposed rats and rats with peri- and postnatal hypoxia exposure, ERα loss-of-function was associated with decreased alveolar size (primarily driven by hypoxic animals) and increased PA remodeling.
Category
Class III. Pulmonary Hypertension Associated with Alveolar Hypoxia
Genetic Factors Associated with Pulmonary Vascular Disease
Animal Models of Pulmonary Vascular Disease and Therapy
Pulmonary Vascular Pathology
Age Focus: No Age-Related Focus
Fresh or Filed Publication: Fresh (PHresh). Less than 1-2 years since publication
Article Access
Free PDF File or Full Text Article Available Through PubMed or DOI: No