Signaling angiogenesis via p42/p44 MAP kinase and hypoxia

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.