Differential Regulation of Pulmonary Vascular Cell Growth by Hypoxia-Inducible Transcription Factor-1α and Hypoxia-Inducible Transcription Factor-2α

Hypoxia-inducible transcription factors HIF-1 alpha and HIF-2 alpha can contribute to pulmonary hypertension and vascular remodeling, but their mechanisms remain unknown. This study investigated the role of HIF-1 alpha and HIF-2 alpha in pulmonary artery endothelial and smooth muscle cells. The exposure of human pulmonary artery endothelial cells (HPAECs) to hypoxia (10% O-2 or 5% O-2) increased proliferation over 48 hours, compared with cells during normoxia (21% O-2). The adenovirus-mediated overexpression of HIF-2 alpha that is transcriptionally active during normoxia (mutHIF-2 alpha) increased HPAEC proliferation, whereas the overexpression of HIF-1 alpha, which is transcriptionally active during normoxia (mutHIF-1 alpha), exerted no effect. The knockdown of HIF-2 alpha decreased proliferation during both hypoxia and normoxia. Both HIFs increased migration toward fibrinogen, used as a chemoattractant. In an angiogenesis tube formation assay, mutHIF-2 alpha-transduced cells demonstrated increased tube formation, compared with the mutHIF-1 alpha-transduced cells. In addition, the tubes formed in HIF-2 alpha-transduced cells were more enduring than those in the other groups. In human pulmonary artery smooth muscle cells (HPASMCs), chronic exposure to hypoxia increased proliferation, compared with cells during normoxia. For HPASMCs transduced with adenoviral HIFs, HIF-1 alpha increased proliferation, whereas HIF-2 alpha exerted no such effect. Thus, HIF-1 alpha and HIF-2 alpha exert differential effects in isolated cells of the human pulmonary vasculature. This study demonstrates that HIF-2 alpha plays a predominant role in the endothelial growth pertinent to the remodeling process. In contrast, HIF-1 alpha appears to play a major role in pulmonary smooth muscle growth. The selective targeting of each HIF in specific target cells may more effectively counteract hypoxic pulmonary hypertension and vascular remodeling.