Hypoxia is a condition defined by low oxygen levels (< 5%) and is a naturally occurring phenomenon during normal embryogenesis. Prior to the formation of a definitive embryonic vasculature and organ system, diffusion from extra-embryonic sites provides the oxygen necessary for development. During organogenesis, the local hypoxic environment seems to serve as a signal for blood vessel formation stimulating the production of angiogenic factors in a manner similar to the induction of angiogenic molecules that accompanies hypoxia in various tumor cells.1 Hemangioblasts (primitive angiogenic cells) differentiate into endothelial cells that begin to form rudimentary tubes or vessels, and into hematopoietic stem cells that embed in the wall of these developing vessels.2, 3 This process (vasculogenesis) precedes the subsequent maturation and remodeling process of angiogenesis.2 One molecule known to be essential for the initiation of vasculogenesis is vascular endothelial growth factor (VEGF). VEGF has pronounced mitogenic activity on vascular elements and is synthesized in response to hypoxia.4
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|Figure 1. Differentiation of hematopoietic cells (HCs) and proper vessel development requires HIF-1-dependent factors. HIF-1 promotes the survival of HCs, which supply VEGF. VEGF induces vasculogenesis by increasing production and proliferation of endothelial cells. Loss of HIF-1 beta/ARNT results in HIF deficiency, increased apoptosis of HCs, reduction in VEGF production and endothelial cell number, and inadequate vessel growth and branching. (Adapted from reference 9).|
HIF-1 (hypoxia inducible factor-1) is a key transcriptional regulator for hypoxic regulation of embryonic vascular development. HIF-1 is an oxygen-sensitive, dimeric complex composed of HIF-1 alpha and HIF-1 beta/ARNT (aryl hydrocarbon receptor nuclear translocator) subunits.5 During conditions of normoxia, HIF-1 beta is found in the nucleus, while HIF-1 alpha is cytoplasmic and rapidly degraded by a ubiquitin-proteosome system. In mammalian cells, reduced oxygen levels permit the accumulation of HIF-1 alpha protein in the cytoplasm. Subsequently, HIF-1 alpha translocates to the nucleus, engages HIF-1 beta, and forms the HIF-1 complex that initiates VEGF transcription and mRNA stabilization.6 Formation of the HIF-1 complex typically occurs during solid tumor formation (increased oxygen demand) and fetal development (inadequate oxygen delivery).
In the fetus, the HIF-1/VEGF connection is a current area of investigation to help explain the larger issue of circulatory system development. Mice lacking HIF-1 activity due to HIF-1 alpha or HIF-1 beta/ARNT null mutations develop extensive cardiovascular defects including inadequate vessel formation and aberrant vascular remodeling.7, 8 The ubiquitous expression pattern and generalized placental function of HIF subunits during embryogenesis confound the analysis of vascular irregularities seen in HIF-deficient embryos. In order to evaluate the role of HIF-1 in vascular and hematopoietic development of the embryo independent of deleterious effects caused by abnormal circulation or placentation, para-aortic splanchnopleural (P-Sp) explant assays have been utilized.9 These P-Sp explants are derived from a site within the embryo where definitive hematopoietic stem cells are committed from hemangioblasts, and the cultures support both angiogenesis and hematopoiesis.10 As compared to those derived from wild type, P-Sp explants from HIF-1 beta/ARNT-/- mice exhibit reduced levels of VEGF protein, increased numbers of apoptotic hematopoietic cells, and abnormal vasculogenesis, angiogenesis, and hematopoiesis.9 When sources for VEGF are added to the system, both endothelial and hematopoietic cell (HC) precursors appear.9 Whether added exogenously or supplied via HCs, VEGF rescues endothelial cell production and vascular morphogenesis (see Figure 1). These results indicate that both decreased survival of, and VEGF production by, HCs contribute to the abnormal vessel development observed in HIF-1 beta/ARNT-/- explants, and suggest that HIF is critical for intraembryonic blood and vessel development.9 These results may complement previous studies identifying HIF-1 signaling via the angiopoietin/Tie-2 system11 and hypoxic regulation of VEGF receptor expression/activity on endothelial cells,12 further elucidating the precise role of HIF-1 during vascular development.
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