Vascular endothelial growth factor and vascular adjustments to perturbations in oxygen homeostasis

Development of microvascular networks is set to meet the metabolic requirem ents of the tissue they perfuse. Accordingly, impairment of oxygen homeosta sis, either due to increased oxygen consumption or as a result of blood ves sel occlusion, triggers compensatory neovascularization. This feedback reac tion is mediated by a hypoxia- and hypoglycemia-induced vascular endothelia l growth factor (VEGF). VEGF accumulates under stress as a result of increa sed hypoxia-inducible factor-1 alpha -mediated transcription, stabilization of the mRNA, and the function of a hypoxia- refractory internal ribosome e ntry site within its 5'-untranslated region. Matching of vascular density t o the metabolic needs of the tissue may include a process of hyperoxia-indu ced vessel regression. Thus newly formed vascular networks may undergo a na tural process of vascular pruning that takes place whenever VEGF, acting as a vascular survival factor, is downregulated below the level required to s ustain immature vessels. Immature vessels are particularly vulnerable and a re selectively obliterated upon withdrawal of VEGF. The plasticity window f or vessel regression is determined by a delay in the recruitment of periend othelial cells to the preformed endothelial plexus. Thus fine-tuning of mic rovascular density takes place mostly in the newly formed plexus, but the m ature system is refractory to episodic changes in tissue oxygenation. These regulatory links may malfunction in certain pathological settings.