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Cardiovascular Research Advance Access [Accepted Manuscript] published online on February 10, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn034
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

ADIPONECTIN INHIBITS VASCULAR ENDOTHELIAL GROWTH FACTOR-INDUCED MIGRATION OF HUMAN CORONARY ARTERY ENDOTHELIAL CELLS

Kalyankar Mahadev1,, Xiangdong Wu1, Sylvia Donnelly1, Raogo Ouedraogo1, Andrea D. Eckhart2 and Barry J. Goldstein1,

1 Division of Endocrinology, Diabetes and Metabolic Diseases, Jefferson Medical College of Thomas Jefferson University, Philadelphia, PA 19107, USA
2 Eugene Feiner Laboratory of Vascular Biology and Thrombosis, Center for Translational Medicine, Department of Medicine, Jefferson Medical College of Thomas Jefferson University, Philadelphia, PA 19107, USA

Address correspondence to either: Barry J. Goldstein, MD, PhD, (HBarry.Goldstein{at}jefferson.edu), Director, Division of Endocrinology, Diabetes and Metabolic Diseases, or Kalyankar Mahadev, PhD, (HMahadev.Kalyankar{at}jefferson.edu), Instructor in Medicine, Department of Medicine, Jefferson Medical College, Suite 320 Curtis Building, 1015 Walnut Street, Philadelphia, PA 19107 USA, Phone: (215)503-1272, FAX: (215) 923-7932

Aims: 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).

Methods and Results: Using a modified Boyden chamber technique and a monolayer "wound-healing" assay, the recombinant adiponectin globular domain and full-length adiponectin protein both potently suppressed HCAEC migration induced by VEGF. Adiponectin did not increase endothelial cell apoptosis, as measured by TUNEL 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 fibers and focal cellular adhesions. VEGF-stimulated cell migration was inhibited by activation of adenylyl cyclase with forskolin, and adiponectin treatment increased cellular cAMP levels and protein kinase A (PKA) enzymatic activity. Pharmacological inhibition of either adenylyl cyclase or PKA significantly abrogated the effect of the adiponectin globular domain to suppress VEGF-induced cell migration.

Conclusion: Adiponectin suppresses VEGF-stimulated HCAEC migration via cAMP/PKA-dependent signaling, an important effect with implications for a regulatory role of adiponectin in vascular processes associated with diabetes and atherosclerosis.

Time for primary review: 27 days


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