New molecular mechanisms of the unexpectedly complex role of VEGF in ulcerative colitis.
The effects of VEGF on endothelial cells are mediated by different intracellular signaling cascades (e.g., Erk1/2, Akt, Src). VEGF plays a recently recognized role in ulcerative colitis (UC) pathogenesis, mostly by increasing vascular permeability and promoting the infiltration of inflammatory cells. We hypothesized that the excessive activation of signal transduction pathways, which is responsible for VEGF/VEGFR-2-mediated endothelial permeability (Src, Akt), is a new element in the pathogenesis of chronic UC. We demonstrated increased expression of pro-angiogenic growth factor VEGF and its receptor VEGFR-2 in colonic tissue during acute 6% iodoacetamide-induced UC in rats and chronic spontaneously developed UC in IL-10 knockout mice (IL-10 KO). Development of acute 6% iodoacetamide-induced UC in rats was accompanied by activation of Erk1/2 and Src kinase, while expression of total proteins Erk1/2 and Src was unchanged. During chronic colitis phosphorylation (i.e., activation) of Erk1/2 was significantly decreased in IL-10 KO mice vs. wild-type mice. Levels of total Erk1/2 proteins were unchanged, but the expression of total Src protein as well as its phosphorylated form was significantly increased in IL-10 KO vs. wild-type mice. There were no changes in total Akt proteins, while levels of activated Akt (pAkt) were slightly increased in IL-10 KO vs. wild-type mice. We conclude that VEGF/VEGFR-2-associated signal transduction pathways, that mediate increased vascular permeability (Src, Akt), might play a central role in perpetuation of chronic experimental UC.
Tolstanova
Ganna
G
Diagnostic & Molecular Medicine Health Care Group, VA Medical Center, and Departments of Pathology and Pharmacology, University of California-Irvine, Long Beach, CA 90822, USA.
Khomenko
Tetyana
T
Deng
Xiaoming
X
Szabo
Sandor
S
Sandor
Zsuzsanna
Z
D000818:Animals; D002199:Capillary Permeability; D003093:Colitis, Ulcerative / Q000139:chemically induced / Q000378:metabolism*; D003106:Colon / Q000187:drug effects / Q000378:metabolism*; D016753:Interleukin-10 / Q000235:genetics; D007460:Iodoacetamide / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
D042461:Vascular Endothelial Growth Factor A; D016753:Interleukin-10; D040301:Vascular Endothelial Growth Factor Receptor-2; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D007460:Iodoacetamide