HIF-dependent hematopoietic factors regulate the development of the embryonic vasculature.
Hypoxia inducible factors (HIFs) regulate adaptive responses to changes in oxygen (O(2)) tension during embryogenesis, tissue ischemia, and tumorigenesis. Because HIF-deficient embryos exhibit a number of developmental defects, the precise role of HIF in early vascular morphogenesis has been uncertain. Using para-aortic splanchnopleural (P-Sp) explant cultures, we show that deletion of the HIF-beta subunit (ARNT) results in defective hematopoiesis and the inhibition of both vasculogenesis and angiogenesis. These defects are rescued upon the addition of wild-type Sca-1(+) hematopoietic cells or recombinant VEGF. Arnt(-/-) embryos exhibit reduced levels of VEGF protein and increased numbers of apoptotic hematopoietic cells. These results suggest that HIF coordinates early endothelial cell emergence and vessel development by promoting hematopoietic cell survival and paracrine growth factor production.
Ramírez-Bergeron
Diana L
DL
Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Runge
Anja
A
Adelman
David M
DM
Gohil
Mercy
M
Simon
M Celeste
MC
D000818:Animals; D017209:Apoptosis; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D001483:Base Sequence; D001808:Blood Vessels / Q000196:embryology*; D001854:Bone Marrow Cells / Q000502:physiology; D018920:Coculture Techniques; D004247:DNA / Q000235:genetics; D047108:Embryonic Development / Q000187:drug effects / Q000502:physiology; D005260:Female; D006410:Hematopoiesis; D016298:Hematopoietic Cell Growth Factors / Q000502:physiology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic; D011247:Pregnancy; D011994:Recombinant Proteins / Q000494:pharmacology; D046509:Tissue Culture Techniques; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism / Q000494:pharmacology
C497397:Arnt protein, mouse; D016298:Hematopoietic Cell Growth Factors; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D004247:DNA