Hypoxia modulates human pulmonary arterial adventitial fibroblast phenotype through HIF-1α activation

Abstract

Hypoxic pulmonary hypertension (HPH) develops in association with diseases characterized by low oxygen levels leading to pulmonary artery (PA) narrowing and death. Hypoxia has been linked to increased PA collagen and changes in PA adventitial fibroblast (PAAF) metabolism. However, the mechanisms by which hypoxia regulates PAAF function are unknown. Hypoxia-inducible factor-1 (HIF-1) is a subunit of a transcription factor that is degraded in normoxia but stabilized in hypoxia and is involved in extracellular matrix remodeling by fibroblasts. We examined the role of hypoxia and HIF-1 in regulating PAAF function. Human PAAF (HPAAF) were cultured in normoxic and hypoxic conditions. Cells were further treated with HIF1- inhibitor or no drug. Protein expression, mRNA expression, enzyme activity, and metabolite concentration were examined. Male C57BL6/J mice were exposed to 0 or 10 days of hypoxia after which right ventricular hemodynamics and tissue metabolism were assessed. Hypoxia led to an increase in collagen content and decrease in matrix metalloproteinase-2 (MMP2) activity. HIF-1 inhibition limited collagen accumulation and restored MMP2 activity. HPAAF demonstrated elevated lactic acid concentration and decreased ATP in hypoxia. HIF-1 inhibition blunted these effects. Mice exposed to hypoxia developed significant elevation in right ventricle systolic pressures and had decreased ATP levels in pulmonary tissue. This study investigated the mechanisms by which hypoxia drives HPAAF-mediated collagen accumulation and metabolic changes. We identify the key role of HIF-1 in regulating changes. These findings provide important insights into understanding HPAAF-mediated PA remodeling and help identify possible novel therapeutic targets.