Premium
Regulation of Cardiovascular Development and Physiology by Hypoxia‐Inducible Factor 1 a
Author(s) -
SEMENZA GREGG L.,
AGANI FATON,
IYER NARAYAN,
KOTCH LORI,
LAUGHNER ERIK,
LEUNG SANDRA,
YU AIMEE
Publication year - 1999
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/j.1749-6632.1999.tb09241.x
Subject(s) - biology , hypoxia inducible factor 1 , hypoxia (environmental) , transcription factor , hypoxia inducible factors , microbiology and biotechnology , vascular endothelial growth factor , gene expression , homeostasis , hif1a , heart development , erythropoietin , regulator , regulation of gene expression , gene , embryonic stem cell , endocrinology , genetics , cancer research , chemistry , organic chemistry , oxygen , vegf receptors
A bstract : Hypoxia is an essential pathophysiologic component of ischemic cardiovascular disease. A better understanding of the molecular mechanisms underlying adaptive responses to hypoxia may lead to novel therapeutic strategies. Hypoxia‐inducible factor 1 (HIF‐1) is a heterodimeric basic‐helix‐loop‐helix‐PAS domain transcription factor that mediates changes in gene expression in response to changes in O 2 concentration. Genes that are transcriptionally activated by HIF‐1 in hypoxic cells encode proteins that increase O 2 delivery or allow metabolic adaptation to limited O 2 availability. HIF‐1 target genes include those encoding vascular endothelial growth factor (VEGF), erythropoietin, glucose transporters, and glycolytic enzymes. In anemic fetal sheep, increased myocardial vascularization was associated with concomitant increases in the expression of HIF‐1 and VEGF. Expression of HIF‐1 target genes was not induced by hypoxia in embryonic stem cells lacking expression of the O 2 ‐regulated HIF‐1αa subunit. Mouse embryos lacking HIF‐1α expression arrested in their development by E9.0 and died by E10.5 with cardiovascular malformations and massive cell death throughout the embryo. These studies indicate that HIF‐1 functions as a master regulator of O 2 homeostasis that controls the establishment of essential physiologic systems during embryogenesis as well as their subsequent utilization during fetal and postnatal life.