Angiogenesis is associated with a number of pathological situations. In thi
s study, we have focused our attention on the role of p42/p44 MAP (mitogen-
activated protein) kinases and hypoxia in the control of angiogenesis. We d
emonstrate that p42/p44 MAP kinases play a pivotal role in angiogenesis by
exerting a determinant action at three levels: i) persistent activation of
p42/p44 MAP kinases abrogates apoptosis; ii) p42/p44 MAP kinase activity is
critical for controlling proliferation and growth arrest of confluent endo
thelial cells; and iii) p42/p44 MAP kinases promote VEGF (vascular endothel
ial growth factor) expression by activating its transcription via recruitme
nt of the AP-2/Sp1 (activator protein-2) complex on the proximal region (-8
8/-66) of the VEGF promoter and by direct phosphorylation of hypoxia-induci
ble factor 1 alpha (HIF-1 alpha). HIF-1 alpha plays a crucial role in the c
ontrol of HIF-1 activity, which mediates hypoxia-induced VEGF expression. W
e show that oxygen-regulated HIF-1 alpha protein levels are not affected by
intracellular localisation (nucleus versus cytoplasm). Finally, we propose
a model which suggests an autoregulatory feedback mechanism controlling HI
F-1 alpha and therefore HIF-1 dependent gene expression. BIOCHEM PHARMACOL
60;8:1171-1178, 2000. (C) 2000 Elsevier Science Inc.