Signaling of hypoxia-induced autonomous proliferation of endothelial cells.
Endothelial cells exhibit an autonomous proliferative response to hypoxia, independent of paracrine effectors. In cultured endothelial cells of porcine aorta, we analyzed the signaling and compared hypoxia with mitochondrial inhibition by rotenone. Particularly, roles of the mitogen-activated protein kinase (MAPK) kinase (MEK)/MAPK pathway and cytosolic Ca2+ were studied. Hypoxia resulted in increased proliferation by 65+/-2%. Hypoxia induced transient activation of p42 MAPK (phosphorylation rose from 11+/-5 to 51+/-7%), followed by translocation of p42 MAPK into the nucleus. The proliferative response was diminished after inhibition of the MEK/MAPK pathway by PD 98059 (20 microM) or UO 126 (10 microM) but not sensitive to 8-phenyl-theophillin (10 microM), an adenosine receptor blocker, nor to a neutralizing antibody for vascular endothelial growth factor (VEGF). Inhibition of intracellular Ca2+ release, capacitive Ca2+ influx, or removal of extracellular Ca2+ prevented hypoxic Ca2+ overload and the proliferative response. Suppression of cytosolic Ca2+ rise did not interfere with activation of p42 MAPK but abolished its nuclear translocation. Effects of hypoxia were mimicked by rotenone (10 microM. Transient hypoxic inhibition of mitochondria induces a proliferative endothelial response mediated through Ca2+-independent activation and Ca2+-dependent nuclear translocation of p42 MAPK. This proliferative response is independent of adenosine or VEGF.
Schäfer
M
M
Institute of Physiology, Justus-Liebig-University, D-35392 Giessen, Germany.
Ewald
N
N
Schäfer
C
C
Stapler
A
A
Piper
H M
HM
Noll
Th
T
D021581:Active Transport, Cell Nucleus; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D002455:Cell Division / Q000187:drug effects; D015687:Cell Hypoxia; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D004727:Endothelium / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D017136:Ion Transport; D020935:MAP Kinase Signaling System; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D008954:Models, Biological; D012402:Rotenone / Q000494:pharmacology; D014475:Uncoupling Agents / Q000494:pharmacology
D014475:Uncoupling Agents; D012402:Rotenone; D019950:Mitogen-Activated Protein Kinase 1; D002118:Calcium