Cellular and developmental control of O₂ homeostasis by hypoxia-inducible factor 1α

Abstract

Hypoxia is an essential developmental and physiological stimulus that plays a key role in the pathophysiology of cancer, heart attack, stroke, and other major causes of mortality. Hypoxia-inducible factor 1 (HIF-1) is the only known mammalian transcription factor expressed uniquely in response to physiologically relevant levels of hypoxia. We now report that in Hif1a −/− embryonic stem cells that did not express the O 2 -regulated HIF-1␣ subunit, levels of mRNAs encoding glucose transporters and glycolytic enzymes were reduced, and cellular proliferation was impaired. Vascular endothelial growth factor mRNA expression was also markedly decreased in hypoxic Hif1a −/− embryonic stem cells and cystic embryoid bodies. Complete deficiency of HIF-1␣ resulted in developmental arrest and lethality by E11 of Hif1a −/− embryos that manifested neural tube defects, cardiovascular malformations, and marked cell death within the cephalic mesenchyme. In Hif1a +/+ embryos, HIF-1␣ expression increased between E8.5 and E9.5, coincident with the onset of developmental defects and cell death in Hif1a −/− embryos. These results demonstrate that HIF-1␣ is a master regulator of cellular and developmental O 2 homeostasis.

The role of oxygen availability in embryonic development and stem cell function

“…Furthermore, ARNT -deficient embryos have decreased VEGF mRNA and protein levels, which implies that VEGF secretion is modulated by naturally low O 2 microenvironments in the early conceptus [22][23][24] . Consistent with these findings, Iyer et al demonstrated that HIF-1α protein can be detected in E8-E18 mouse embryos 25 ; HIF-1α -deficient embryos show similar phenotypes to Arnt −/− mice, with defects in blood vessel formation and neural fold closure 25,26 .…”

Vascular endothelial growth factor in eye disease

“…When this occurs, HIF-1α complexes with HIF-1β, translocates into the nucleus and binds to a specific sequence in the 5′ flanking region of the VEGF gene, the hypoxia responsive element (HRE) (Ikeda et al, 1995;Laughner et al, 2001;Shima et al, 1996;Wenger, 2002;Forsythe et al, 1996). The importance of interaction between HIF-1α and the VEGF promoter has been confirmed in studies of HIF-1α −/− mouse embryonic stem cells, in which basal expression of VEGF mRNA remains low in response to hypoxia (Carmeliet et al, 1998;Iyer et al, 1998).…”

The HIF-2α-Driven Pseudo-Hypoxic Phenotype in Tumor Aggressiveness, Differentiation, and Vascularization

“…In the dimeric, active state, HIF-1 and HIF-2 bind to hypoxia responsive elements (HREs) located in genes regulated by hypoxia and HIFs. Although HIF-1 and HIF-2 seem to activate hypoxiaresponsive genes by similar means (Tian et al 1997;Wiesener et al 1998), the HIF-α subunits work in a non-redundant manner and several differences in gene regulation have been proposed, many of which emphasize the predominant role of HIF-1 in regulating the transcriptional response to hypoxia (Iyer et al 1998;Ryan et al 1998;Hu et al 2003;Park et al 2003;Sowter et al 2003). As detailed below, HIF-2 is also crucial for the hypoxic response, and, as opposed to HIF-1, it is active at prolonged hypoxia as well (HolmquistMengelbier et al 2006).…”