title: Uncoupling of vascular endothelial growth factor with nitric oxide as a mechanism for diabetic vasculopathy.
abstract: The role of VEGF in vascular disease is complicated. Vascular endothelial growth factor (VEGF) expression can be deleterious in diabetic vasculopathy, especially in kidney and retina. In contrast, VEGF seems to be renoprotective in nondiabetic renal disease. VEGF exerts it biologic effects in association with nitric oxide (NO), yet it is known that NO bioavailability is reduced in diabetes. Thus, it was hypothesized that this diverse biologic effect of VEGF on diabetic vasculopathy is due to uncoupling of VEGF with NO. VEGF stimulated NO production in a dose-dependent manner in bovine aortic endothelial cells (BAEC), and this was inhibited by either high glucose or Nomega-nitro-l-arginine methyl ester (L-NAME) treatment. Endothelial NO synthase phosphorylation by VEGF was also inhibited by high glucose. It is interesting that both high glucose and L-NAME enhanced the proliferative response of endothelial cells, which was prevented by an NO donor. Furthermore, high glucose as well as L-NAME stimulated VEGF and kinase-insert domain receptor (KDR) (VEGF receptor 2) mRNA expression in BAEC. These data suggest that the uncoupling of VEGF with NO enhances endothelial cell proliferation via the KDR pathway. Compatible with these findings, a KDR antagonist blocked this response. In addition, a VEGF mutant, which binds only KDR, induced extracellular signal-regulated kinase (ERK) activation, and inhibition of ERK completely blocked endothelial cell proliferation under this condition, suggesting a role of the KDR-ERK1/2 pathway on endothelial cell proliferation. In conclusion, high glucose causes an uncoupling of VEGF with NO, which enhances endothelial cell proliferation via activation of the KDR-ERK1/2 pathway. These results may provide new insights into the understanding of the mechanism of diabetic vascular disease.
authors.affiliation: Division of Nephrology, Hypertension and Transplantation, University of Florida, PO Box 100224, Gainesville, FL 32610, USA. nakagt@medicine.ufl.edu
authors.forename: Takahiko
authors.initials: T
authors.lastname: Nakagawa
authors.forename: Waichi
authors.initials: W
authors.lastname: Sato
authors.forename: Yuri Y
authors.initials: YY
authors.lastname: Sautin
authors.forename: Olena
authors.initials: O
authors.lastname: Glushakova
authors.forename: Byron
authors.initials: B
authors.lastname: Croker
authors.forename: Mark A
authors.initials: MA
authors.lastname: Atkinson
authors.forename: C Craig
authors.initials: CC
authors.lastname: Tisher
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Johnson
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002417:Cattle; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003925:Diabetic Angiopathies / Q000503:physiopathology*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000032:analysis / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D012016:Reference Values; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012680:Sensitivity and Specificity; D042442:Vascular Endothelial Growth Factors / Q000494:pharmacology*
chemical_list: D012333:RNA, Messenger; D042442:Vascular Endothelial Growth Factors; D009569:Nitric Oxide; D020928:Mitogen-Activated Protein Kinases; D019331:NG-Nitroarginine Methyl Ester