Hypoxia Inducible Factor-1α in Pulmonary Artery Smooth Muscle Cells Lowers Vascular Tone by Decreasing Myosin Light Chain Phosphorylation
Rationale: Hypoxia inducible factor-1αHIF-1α an oxygen (O2)-sensitive transcription factor, mediates transcriptional responses to low O2 tension states. While acute hypoxia causes pulmonary vasoconstriction and chronic hypoxia can cause vascular remodeling and pulmonary hypertension, conflicting data exists surrounding the role of HIF-1α in modulating pulmonary vascular tone.
Objective: To investigate the role of smooth muscle cell (SMC) specific HIF-1α in regulating pulmonary vascular tone.
Methods and Results: Mice with a SMC specific deletion of HIF-1α (SM22α-HIF-1α-/-) were created to test the hypothesis that pulmonary artery smooth muscle cell (PASMC) HIF-1α modulates pulmonary vascular tone and the response to hypoxia. SM22α-HIF-1α-/- mice exhibited significantly higher right ventricular systolic pressure (RVSP) compared to wild-type (WT) littermates under normoxia and with exposure to either acute or chronic hypoxia in the absence of histologic evidence of accentuated vascular remodeling. Moreover, myosin light chain (MLC) phosphorylation, a determinant of SMC tone, was higher in PASMC isolated from SM22α-HIF-1α-/- mice compared to WT PASMC, during both normoxia and after acute hypoxia. Further, over-expression of HIF-1α decreased MLC phosphorylation in HIF-1α-null SMC.
Conclusions: In both normoxia and hypoxia, PASMC HIF-1α maintains low pulmonary vascular tone by decreasing MLC phosphorylation. Compromised PASMC HIF-1α expression may contribute to the heightened vasoconstriction that characterizes pulmonary hypertension.
- oxygen sensing
- hypertension, pulmonary
- hypoxia-inducible factor 1 (HIF-1)
- vascular tone regulation
- Received November 29, 2012.
- Revision received March 18, 2013.
- Accepted March 19, 2013.