| First Author | Barnes EA | Year | 2023 |
| Journal | Am J Physiol Lung Cell Mol Physiol | Volume | 325 |
| Issue | 6 | Pages | L741-L755 |
| PubMed ID | 37847687 | Mgi Jnum | J:342470 |
| Mgi Id | MGI:7545413 | Doi | 10.1152/ajplung.00428.2022 |
| Citation | Barnes EA, et al. (2023) Loss of Prolyl Hydroxylase 1 and 2 in SM22alpha-Expressing Cells Prevents Hypoxia-Induced Pulmonary Hypertension. Am J Physiol Lung Cell Mol Physiol |
| abstractText | 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-1alpha (HIF-1alpha), yet the role of PASMC HIF-1alpha in the development of PAH remains controversial. To study the role of SMC HIF-1alpha in the pulmonary vascular response to acute and chronic hypoxia, we employed a gain of function strategy to stabilize HIF-1alpha in PASMC by generating mice lacking prolyl hydroxylase domain (PHD) 1 and 2 in SM22alpha-expressing cells. This strategy increased HIF-1alpha expression and transcriptional activity under conditions of normoxia and hypoxia. Acute hypoxia increased right ventricular systolic pressure (RVSP) in control, but not in SM22alpha-PHD1/2(-/-) mice. Chronic hypoxia increased RVSP and vascular remodeling more in control SM22alpha-PHD1/2(+/+) than in SM22alpha-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 SM22alpha-PHD1/2(-/-) compared to SM22alpha-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 SM22alpha-expressing cell specific role for HIF-1alpha in the inhibition of pulmonary vasoconstriction and vascular remodeling. Modulating HIF-1alpha expression in PASMC may represent a promising preventative and therapeutic strategy for patients with PAH. |
