A cellular paradigm for the failure to increase vascular endothelial growth factor in chronically hypoxic states.
BACKGROUND
Angiogenesis, or new blood vessel formation, is the physiological adaptation of a tissue to hypoxia or ischemia. However, this compensatory response to hypoxic stress in vivo is often insufficient. In many of the conditions in which the angiogenic response to tissue hypoxia is insufficient, such as chronic critical limb ischemia or myocardial hibernation, the hypoxic stress is chronic and persistent, lasting for days or even months. Vascular endothelial growth factor (VEGF) has been demonstrated in vivo and in vitro to be the principal mediator of hypoxia-induced angiogenesis. We propose that the lack of compensatory angiogenesis in response to tissue hypoxia in many clinical syndromes characterized by chronic hypoxia is due to a failure to induce VEGF appropriately.


RESULTS
Heart or liver cells were grown under conditions of chronic hypoxia, returned to a normoxic environment, and then rechallenged with hypoxia. We found that the hypoxic induction of VEGF mRNA was markedly blunted using this algorithm. Furthermore, transient transfection studies using the VEGF promoter containing an oxygen-responsive enhancer element failed to show induction in cells pretreated by subjection to chronic hypoxia.


CONCLUSIONS
Hypoxic pretreatment results in a blunting of the ability of a cell to induce VEGF in response to subsequent episodes of hypoxia. This may provide a rationale for the inadequate amount of compensatory angiogenesis seen in many chronic ischemic disorders.
Levy
A P
AP
Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel. alevy@tx.technion.ac.il
D000818:Animals; D002470:Cell Survival; D002478:Cells, Cultured; D016228:Endothelial Growth Factors / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D008099:Liver / Q000166:cytology* / Q000378:metabolism; D008222:Lymphokines / Q000096:biosynthesis* / Q000235:genetics; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D008222:Lymphokines; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors