HYPOXIA-INDUCED EXPRESSION OF VEGF IS REVERSIBLE IN MYOCARDIAL VASCULAR SMOOTH-MUSCLE CELLS

We determined whether hypoxia-induced expression of vascular endotheli al growth factor (VEGF) can be reversed by a normoxic environment. Dog myocardial vascular smooth muscle cells (MVSMCs) were exposed to hypo xia (1% O-2) for 24 h and then returned to normoxia (20% O-2) VEGF pro tein levels increased by more than fivefold after 24 h of hypoxia and returned to baseline within 24 h of the return of the cells to normoxi a. Northern blot analysis showed that hypoxia caused a 5.5-fold increa se in VEGF mRNA, and, again, the expression was reversed after reinsti tution of normoxia. Additional measurements showed that basic fibrobla st growth factor and platelet-derived growth factor protein levels wer e not induced by hypoxia and that hypoxia caused a fourfold decrease i n transforming growth factor-beta 1 protein levels. Hypoxia conditione d media from MVSMCs caused human umbilical vein endothelial cells to i ncrease [H-3]thymidine incorporation by twofold, an effect that was bl ocked in a dose-dependent manner by anti-human VEGF antibody. The hypo xia conditioned media had no effect on MVSMC proliferation. These find ings suggest that VEGF expression can be bidirectionally controlled by tissue oxygenation, and thus support the hypothesis that VEGF is a ph ysiological regulator of angiogenesis.