p38 MAPK inhibition is critically involved in VEGFR-2-mediated endothelial cell survival.
Vascular endothelial growth factor (VEGF) promotes vasculogenesis, arteriogenesis, and angiogenesis by stimulating proliferation, migration, and cell survival of endothelial cells. VEGF mediates its actions through activation of two receptor tyrosine kinases, VEGFR-1 and VEGFR-2. Serum starvation led to apoptosis of human umbilical vein endothelial cells (HUVEC), which was accompanied by activation of p38 MAPK and caspase-3. Stimulation of both VEGF-receptors resulted in a considerable decrease of apoptosis, which was associated with the inhibition of p38 MAPK and caspase-3 activity. Selective stimulation of VEGFR-2 showed similar results, whereas the isolated activation of VEGFR-1 was without effect. Incubation of HUVEC with SB203580, a p38 MAPK inhibitor, resulted in similar effects as VEGF-stimulation: p38 MAPK and caspase-3 enzyme activity were reduced and apoptosis was prevented. These data indicate that activation of VEGFR-2 prevents endothelial cell apoptosis by inhibiting p38 MAPK phosphorylation and thus, reducing caspase-3 activity.
Yilmaz
Ali
A
Department of Internal Medicine II (Cardiology), Ulm University Medical Center, University of Ulm, Robert-Koch-Str 8, 89081, Ulm, Germany.
Kliche
Stefanie
S
Mayr-Beyrle
Ulrike
U
Fellbrich
Guido
G
Waltenberger
Johannes
J
D017209:Apoptosis / Q000502:physiology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000502:physiology*; D016895:Culture Media, Serum-Free; D016228:Endothelial Growth Factors / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D004789:Enzyme Activation; D006801:Humans; D007093:Imidazoles / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008222:Lymphokines / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011725:Pyridines / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*; D042442:Vascular Endothelial Growth Factors; D048051:p38 Mitogen-Activated Protein Kinases
D016895:Culture Media, Serum-Free; D016228:Endothelial Growth Factors; D007093:Imidazoles; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D011725:Pyridines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D040301:Vascular Endothelial Growth Factor Receptor-2; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; C093642:SB 203580