Abstract

Hypoxia-inducible factor-1a (HIF-1a), an oxygen (O2)-sensitive transcription factor, mediates transcriptional responses to low-O2 tension states. Although acute hypoxia causes pulmonary vasoconstriction and chronic hypoxia can cause vascular remodeling and pulmonary hypertension, conflicting data exist on the role of HIF-1a in modulating pulmonary vascular tone.To investigate the role of smooth muscle cell (SMC)-specific HIF-1a in regulating pulmonary vascular tone.Mice with an SMC-specific deletion of HIF-1a (SM22a-HIF-1a(-/-)) were created to test the hypothesis that pulmonary artery SMC (PASMC) HIF-1a modulates pulmonary vascular tone and the response to hypoxia. SM22a-HIF-1a(-/-) mice exhibited significantly higher right ventricular systolic pressure compared with wild-type littermates under normoxia and with exposure to either acute or chronic hypoxia in the absence of histological evidence of accentuated vascular remodeling. Moreover, myosin light chain phosphorylation, a determinant of SMC tone, was higher in PASMCs isolated from SM22a-HIF-1a(-/-) mice compared with wild-type PASMCs, during both normoxia and after acute hypoxia. Further, overexpression of HIF-1a decreased myosin light chain phosphorylation in HIF-1a-null SMCs.In both normoxia and hypoxia, PASMC HIF-1a maintains low pulmonary vascular tone by decreasing myosin light chain phosphorylation. Compromised PASMC HIF-1a expression may contribute to the heightened vasoconstriction that characterizes pulmonary hypertension.

View details for DOI 10.1161/CIRCRESAHA.112.300646

View details for PubMedID 23513056

View details for PubMedCentralID PMC4005857