Adiponectin inhibits vascular endothelial growth factor-induced migration of human coronary artery endothelial cells.
OBJECTIVE
Vascular endothelial growth factor (VEGF)-induced endothelial cell migration and angiogenesis are associated with the vascular complications of diabetes mellitus, and adiponectin is an abundant plasma adipokine that exhibits salutary effects on endothelial function. We investigated whether adiponectin suppresses VEGF-induced migration and related signal transduction responses in human coronary artery endothelial cells (HCAECs).


RESULTS
Using a modified Boyden chamber technique and a monolayer 'wound-healing' assay, both the recombinant adiponectin globular domain and full-length adiponectin protein potently suppressed the migration of HCAEC induced by VEGF. Adiponectin did not increase endothelial cell apoptosis, as measured by terminal deoxynucleotidyl transferase biotin-dUTP Nick End Labelling assay. Adiponectin also suppressed VEGF-induced reactive oxygen species generation, activation of Akt, the mitogen-activated protein kinase ERK and the RhoGTPase RhoA, and induction of the formation of actin stress fibres and focal cellular adhesions. VEGF-stimulated cell migration was inhibited by activation of adenylyl cyclase with forskolin, and adiponectin treatment increased cellular cyclic adenosine monophosphate (cAMP) levels and protein kinase A (PKA) enzymatic activity. Pharmacological inhibition of either adenylyl cyclase or PKA significantly abrogated the effect of adiponectin globular domain to suppress VEGF-induced cell migration.


CONCLUSIONS
Adiponectin suppresses VEGF-stimulated HCAEC migration via cAMP/PKA-dependent signalling, an important effect with implications for a regulatory role of adiponectin in vascular processes associated with diabetes and atherosclerosis.
Mahadev
Kalyankar
K
Division of Endocrinology, Diabetes and Metabolic Diseases, Department of Medicine, Jefferson Medical College, Thomas Jefferson University, Suite 320, Curtis Building, 1015 Walnut Street, Philadelphia, PA 19107, USA. mahadev.kalyankar@jefferson.edu
Wu
Xiangdong
X
Donnelly
Sylvia
S
Ouedraogo
Raogo
R
Eckhart
Andrea D
AD
Goldstein
Barry J
BJ
D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000378:metabolism; D052242:Adiponectin / Q000378:metabolism; D017209:Apoptosis; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D022001:Focal Adhesions / Q000378:metabolism; D006801:Humans; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D022502:Stress Fibers / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D014945:Wound Healing; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
C499918:ADIPOQ protein, human; D000067956:Adenylyl Cyclase Inhibitors; D052242:Adiponectin; D020536:Enzyme Activators; D004791:Enzyme Inhibitors; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D000242:Cyclic AMP; D051057:Proto-Oncogene Proteins c-akt; D017868:Cyclic AMP-Dependent Protein Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020742:rhoA GTP-Binding Protein; D000262:Adenylyl Cyclases