Coexpression of endothelial PAS protein 1 with essential angiogenic factors suggests its involvement in human vascular development

Abstract

Endothelial PAS protein 1 (EPAS1) is a bHLH-PAS transcription factor involved in cellular response to hypoxia. Its precise role in angiogenesis is unclear, but several genes essential to vascular development, including those encoding vascular endothelial growth factor (VEGF), its receptor VEGFR-2 and Tie2, are thought to be targets of EPAS1. To investigate whether this transcription factor and its putative targets were expressed concomitantly, we performed in situ hybridization on serial adjacent sections of human embryos at gestational ages of 3 to 6 weeks. We studied expression of the genes encoding EPAS1, VEGF, VEGFR-1, and -2, Tie2, and its ligands, angiopoietin (Ang) 1 and 2. We also compared these expression profiles with that of hypoxia-inducible factor 1␣ (HIF1␣). EPAS1 transcripts were detected in several types of endothelial cell: in blood vessels walls, the endocardium, the glomeruli of the mesonephros, and the sinusoids of the liver. In these endothelial cells, expression of EPAS1 systematically or partly coincided with Tie2 and the VEGF receptors expression. There was also some overlap between the sites of synthesis of EPAS1 and VEGF mRNAs, principally in hepatocytes and sympathetic ganglion cells. In addition, we found that EPAS1 and HIF1␣ transcripts were often colocalized, suggesting a functional redundancy of these two transcription factors during development. These observations are consistent with transactivation by EPAS1 of the expression of its putative target genes during embryogenesis, suggesting that this transcription factor is involved in human angiogenesis. They provide evidence that EPAS1 is involved in the regulation of vascular maturation, remodeling, or stabilization rather than in the early steps of embryonic angiogenesis.

Targeted Replacement of Hypoxia-Inducible Factor-1α by a Hypoxia-Inducible Factor-2α Knock-in Allele Promotes Tumor Growth

“…The hypoxically regulated transcription factors HIF-1a and HIF-2a are overexpressed in a large number of human tumor types, including brain, prostate, breast, RCC, pheochromocytomas, astrocytomas, and non-small cell lung cancers (21,(42)(43)(44), consistent with the idea that each contributes to tumor growth by activating the expression of critical target genes. Although both HIF-1a and HIF-2a are expressed in many of the same human tumors and tumor cell lines (29,45), the relative contribution of each protein to tumor initiation and progression has been difficult to determine.…”

Endometrium as an early sensor of in vitro embryo manipulation technologies

“…As an illustration, EPAS1 or CALB3 were found to be up-regulated in the IC and the C areas of SCNT recipient cows respectively. EPAS1 (also known as HIF-2 ␣) is a transcription factor participating to the cellular response to hypoxia, stabilizing the vascular maturation in human angiogenesis (19) and increased with preeclampsia in women endometrium (20). The role of EPAS1 in the bovine placentation is not yet established but EPAS1 up-regulation in SCNT pregnancies is in keeping with the increase of HIF-1␣ recently reported in bovine SCNT pregnancies at day 30 (21).…”

HIF-2α regulates Oct-4: effects of hypoxia on stem cell function, embryonic development, and tumor growth

“…HIF-1␣ and HIF-2␣ are overexpressed in a large number of human tumor types, including brain, breast, RCC carcinomas, pheochromoctyomas, astrocytomas, and non-small-cell lung cancers (Favier et al 2001;Giatromanolaki et al 2001;Jaakkola et al 2001;Khatua et al 2003). Several experiments have shown that expression of HIF-2␣ promotes more rapid growth of RCC xenografts (Kondo et al 2002(Kondo et al , 2003Maranchie et al 2002;Raval et al 2005) and ES cell-derived teratomas (Covello et al 2005) than does expression of HIF-1␣.…”