Elizabeth A. Barnes, Reiji Ito, Xibing Che, Cristina M. Alvira, David N. Cornfield
Stanford University.
United States and Japan
American Journal of Physiology Lung Cellular and Molecular Physiology
Am J Physiol Lung Cell Mol Physiol 2023;
DOI: 10.1152/ajplung.00428.2022
Abstract
Pulmonary arterial hypertension (PAH) is a disease characterized by increased vasoconstriction and vascular remodeling. Pulmonary artery smooth muscle cells (PASMC) highly express the transcription factor hypoxia inducible factor-1α (HIF-1α), yet the role of PASMC HIF-1α in the development of PAH remains controversial. To study the role of SMC HIF-1α in the pulmonary vascular response to acute and chronic hypoxia, we employed a gain of function strategy to stabilize HIF-1α in PASMC by generating mice lacking prolyl hydroxylase domain (PHD) 1 and 2 in SM22α-expressing cells. This strategy increased HIF-1α expression and transcriptional activity under conditions of normoxia and hypoxia. Acute hypoxia increased right ventricular systolic pressure (RVSP) in control, but not in SM22α-PHD1/2-/- mice. Chronic hypoxia increased RVSP and vascular remodeling more in control SM22α-PHD1/2+/+ than in SM22α-PHD1/2-/- mice. In vitro studies demonstrated increased contractility and myosin light chain phosphorylation in isolated PHD1/2+/+ compared to PHD1/2-/- PASMC under both normoxic and hypoxic conditions. After chronic hypoxia there was more p27 and less vascular remodeling in SM22α-PHD1/2-/- compared to SM22α-PHD1/2+/+ mice. Hypoxia increased p27 in PASMC isolated from control patients, but not in cells from patients with idiopathic PAH (IPAH). These findings highlight a SM22α-expressing cell specific role for HIF-1α in the inhibition of pulmonary vasoconstriction and vascular remodeling. Modulating HIF-1α expression in PASMC may represent a promising preventative and therapeutic strategy for patients with PAH.
Category
Vascular Cell Biology and Mechanisms of Pulmonary Vascular Disease
Animal Models of Pulmonary Vascular Disease and Therapy
Class III. Pulmonary Hypertension Associated with Alveolar Hypoxia
Age Focus: No Age-Related Focus
Fresh or Filed Publication: Filed (PHiled). Greater than 1-2 years since publication
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