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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:773.)
© 2006 American Heart Association, Inc.

Vascular Biology

Tetrapeptide AcSDKP Induces Postischemic Neovascularization Through Monocyte Chemoattractant Protein-1 Signaling

Ludovic Waeckel; Jérôme Bignon; Jian-Miao Liu; Delphine Markovits; Téni G. Ebrahimian; José Vilar; Barend Mees; Olivier Blanc-Brude; Véronique Barateau; Sophie Le ricousse-Roussanne; Micheline Duriez; Gérard Tobelem; Joanna Wdzieczak-Bakala; Bernard I Lévy; Jean-Sébastien Silvestre

From the Cardiovascular Research Center (L.W., T.G.E., J.V., O.B.-B., M.D., B.I.L., J.-S.S.), INSERM U689, Université Paris 7, Paris, France; UPR 2301 CNRS (J.B., J.-M.L., D.M., J.W.-B.), Gif-sur-Yvette, France; Institut des Vaisseaux et du Sang (V.B., S.L.-R., G.T.), Hôpital Lariboisière, Paris, France; and the Department of Vascular Surgery (B.M.), Department.of Cell Biology & Genetics Erasmus University Medical Center Rotterdam, the Netherlands.

Correspondence to Jean-Sebastien Silvestre, U689 INSERM, Hôpital Lariboisière, 41 Bd de la Chapelle, 75475 Paris cedex 10, France. E-mail Jean-Sebastien.Silvestre{at}larib.inserm.fr

Background— We investigated the putative proangiogenic activity and molecular pathway(s) of the tetrapeptide acetyl-N-Ser-Asp-Lys-Pro (AcSDKP) in a model of surgically induced hindlimb ischemia.

Methods and Results— Hindlimb ischemia was induced by femoral artery ligature and an osmotic minipump was implanted subcutaneously to deliver low (0.12 mg/kg per day) or high (1.2 mg/kg per day) doses of AcSDKP, for 7 or 21 days. Angiography scores, arteriole density, capillary number, and foot perfusion were increased at day 21 in the high-dose AcSDKP-treated mice (by 1.9-, 1.8-, 1.3-, and 1.6-fold, respectively) compared with control animals (P<0.05, P<0.01, P<0.01, respectively). AcSDKP treatment for 24 hours upregulated the monocyte chemoattractant protein-1 (MCP-1) mRNA and protein levels by 1.5-fold in cultured endothelial cells (P<0.01). In the ischemic hindlimb model, administration of AcSDKP also enhanced MCP-1 mRNA levels by 90-fold in ischemic leg (P<0.001) and MCP-1 plasma levels by 3-fold (P<0.001 versus untreated ischemic control mice). MCP-1 levels upregulation were associated with a 2.3-fold increase in the number of Mac3-positive cells in ischemic area of AcSDKP-treated mice (P<0.001 versus untreated animals). Interestingly, AcSDKP-induced monocyte/macrophage infiltration and postischemic neovascularization was fully blunted in MCP-1-deficient animals.

Conclusion— AcSDKP stimulates postischemic neovascularization through activation of a proinflammatory MCP-1-related pathway.

In this study, we investigated the putative proangiogenic activity and molecular pathway(s) of the tetrapeptide acetyl-N-Ser-Asp-Lees-Pro (AcSDKP) in a model of surgically induced hind limb ischemia. AcSDKP stimulated MCP-1 mRNA and protein levels in cultured endothelial cells and ischemic tissue. Subsequently, AcSDKP-induced MCP-1 upregulation activated monocytes/macrophages infiltration to ischemic areas and promoted postischemic neovascularization.

Key Words: angiogenesis • ischemia • inflammation • AcSDKP • MCP-1