P310	The tetrapeptide AcSDKP induces post-ischemic neovascularization through monocyte chemoattractant protein-1 signaling.
1L.Waeckel, 2J.Bignon, 2D.Markovits, 2J-M.Liu, 1T.G.Ebrahimian, 1J.Vilar, 1O.Blanc-Brude, 2J.Wdzieczak-Bakala, 1B.I.Lévy, 1J-S.Silvestre
1Cardiovascular Research Center Inserm U689, Paris, FR; 2CNRS, Gif-sur-Yvette, FR.

Introduction. The tetrapeptide acetyl-N-Ser-Asp-Lys-Pro (AcSDKP) is a naturally peptide present in blood at nanomolar concentration and ubiquitously distributed in various tissues. Little is known about its physiological function. AcSDKP has been shown to activate endothelial cell migration and angiogenesis in the Matrigel model. We hypothesized that AcSDKP may promote post-ischemic neovascularization. Methods and Results. Ischemia was produced by femoral artery ligature and an osmotic minipump was implanted subcutaneously to deliver low (2.4 mg) or high (24 mg) doses of AcSDKP, for 7 or 21 days (n=7 per groups). Neovascularization was unchanged by AcSDKP administration after 7 days of treatment. In contrast, angiography scores, capillary numbers and foot perfusion were increased at day 21 in high dose AcSDKP-treated mice by 1.9-, 1.3-, and 1.6-fold, respectively compared to control animals (p<0.05, p<0.01, p<0.01, respectively). We next attempted to define the cellular and molecular pathway involved in the pro-angiogenic effect of AcSDKP. AcSDKP (10-7 M to 10-11 M) did not affect endothelial cells proliferation, as assessed by H3-thymidin incorporation. Alternatively, 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 9-fold in ischemic leg (p<0.001) and MCP-1 plasma levels by 3-fold compared with untreated ischemic control mice (p<0.001). Finally, MCP-1 positive staining was mainly detected around capillaries in ischemic tissues and was markedly improved by AcSDKP treatment.These effects 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/macrophages infiltration and post-ischemic neovascularization was fully blunted in AcSDKP-treated MCP-1-deficient animals. Conclusion. These results suggest that AcSDKP enhances MCP-1 production by endothelial cells and thereby attracts monocytes/macrophages within ischemic area to activate neovascularization.

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