Loss of prolyl hydroxylase 1 and 2 in SM22-expressing cells prevents Hypoxia-Induced pulmonary hypertension

Pulmonary arterial hypertension (PAH) is a disease characterized by increased vasoconstriction and vascular remodeling. Pulmonary artery smooth muscle cells (PASMCs) highly express the transcription factor hypoxia-inducible factor-1 alpha (HIF-1 alpha), yet the role of PASMC HIF-1 alpha in the development of PAH remains controversial. To study the role of SMC HIF-1 alpha in the pulmonary vascular response to acute and chronic hypoxia, we used a gain-of-function strategy to stabilize HIF-1 alpha in PASMC by generating mice lacking prolyl hydroxylase domain (PHD) 1 and 2 in SM22 alpha-expressing cells. This strategy increased HIF-1 alpha expression and transcriptional activity under conditions of normoxia and hypoxia. Acute hypoxia increased right ventricular systolic pressure (RVSP) in control, but not in SM22 alpha-PHD1/2(-/-) mice. Chronic hypoxia increased RVSP and vascular remodeling more in control SM22 alpha-PHD1/2(+/+) than in SM22 alpha-PHD1/2(-/-) mice. In vitro studies demonstrated increased contractility and myosin light chain phosphorylation in isolated PHD1/2(+/+) compared with PHD1/2(-/-) PASMC under both normoxic and hypoxic conditions. After chronic hypoxia, there was more p27 and less vascular remodeling in SM22 alpha-PHD1/2(-/-) compared with SM22 alpha-PHD1/2(+/+) mice. Hypoxia increased p27 in PASMC isolated from control patients, but not in cells from patients with idiopathic pulmonary arterial hypertension (IPAH). These findings highlight an SM22 alpha-expressing cell-specific role for HIF-1 alpha in the inhibition of pulmonary vasoconstriction and vascular remodeling. Modulating HIF-1 alpha expression in PASMC may represent a promising preventative and therapeutic strategy for patients with PAH.NEW & NOTEWORTHY In a mouse model wherein hypoxia-inducible factor 1 alpha (HIF-1 alpha) is stabilized in vascular smooth muscle cells, we found that HIF-1 alpha regulates vasoconstriction by limiting phosphorylation of myosin light chain and regulates vascular remodeling through p27 induction. These findings highlight a cell-specific role for HIF-1 alpha in the inhibition of pulmonary vasoconstriction and vascular remodeling.