JNK as a positive regulator of angiogenic potential in endothelial cells.
Angiogenesis (the growth of new capillaries) occurs in adults in response to physiological stimuli such as wound healing and exercise. The mitogen-activated protein kinase c-jun N-terminal kinase (JNK) has a controversial role in the process of angiogenesis, with previous evidence supporting JNK as both a positive and negative regulator of blood vessel growth. The purpose of this study was to clarify the role of JNK in the angiogenesis process. Phosphorylated JNK was observed in cultured endothelial cells, and levels were constant regardless of extracellular matrix composition. Using SP600125, inhibition of JNK attenuated sprout growth in 3D capillary sprout cultures. Inhibition of JNK reduced endothelial cell proliferation and migration in vitro. JNK inhibition and siRNA knockdown of c-jun (a downstream target of JNK) decreased protein levels of the transcription factor Egr-1, a regulator of genes involved in proliferation and migration. Matrix metalloproteinase-2 (MMP-2) production, and activity also, was reduced in sprout cultures treated with SP600125. c-Jun silencing decreased both MMP-2 and membrane type-1 (MT1)-MMP mRNA in endothelial cells, implicating both JNK and c-jun as activators of proteolysis. Taken together, these results provide evidence that JNK and its downstream target c-jun positively regulate angiogenesis via activation of endothelial cell proliferation, migration and proteolysis.
Uchida
Cassandra
C
School of Kinesiology and Health Sciences, York University, Farquharson Room 341, 4700 Keele Street, Toronto, ON, Canada M3J 1P3.
Gee
Eric
E
Ispanovic
Eric
E
Haas
Tara L
TL
D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D051766:Early Growth Response Protein 1 / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology* / Q000502:physiology; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000187:drug effects; D051381:Rats
D000873:Anthracenes; D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; C432165:pyrazolanthrone; D048031:JNK Mitogen-Activated Protein Kinases; D020778:Matrix Metalloproteinase 2