Loss of smooth muscle cell hypoxia inducible factor-1a underlies increased vascular contractility in pulmonary hypertension

Abstract

Pulmonary arterialhypertension(PAH) is an often fatal disease with limited treatment options.Whereas current data support the notion that, in pulmonary artery endothelial cells (PAECs), expression of transcription factor hypoxia inducible factor-1α (HIF-1α) is increased, the role of HIF-1α in pulmonary artery smooth muscle cells (PASMCs) remains controversial. This study investigates the hypothesis that, in PASMCs from patients with PAH, decreases in HIF-1a expression and activity underlie augmented pulmonary vascular contractility. PASMCs and tissues were isolated fromnonhypertensive control patients and patients with PAH. Compared with controls, HIF-1a and Kv1.5 protein expression were decreased in PAH smooth muscle cells (primary culture). Myosin light chain (MLC) phosphorylation and MLC kinase (MLCK) activity-major determinants of vascular tone-were increased in patients with PAH. Cofactors involved in prolyl hydroxylase domain activity were increased in PAH smoothmuscle cells. Functionally, PASMCcontractilitywas inversely correlated with HIF-1a activity. InPASMCs derived from patients with PAH, HIF-1α expression is decreased, and MLCK activity, MLC phosphorylation, and cell contraction are increased. We conclude that compromised PASMC HIF-1α expression may contribute to the increased tone that characterizes pulmonary hypertension.-Barnes, E.A., Chen, C.-H., Sedan, O., Cornfield, D.N. Loss of smooth muscle cell hypoxia inducible factor-1a underlies increased vascular contractility in pulmonary hypertension FASEB J. 31, 650-662 (2017). www.fasebj.org.