Tetrapeptide AcSDKP induces postischemic neovascularization through monocyte chemoattractant protein-1 signaling.
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.


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.


CONCLUSIONS
AcSDKP stimulates postischemic neovascularization through activation of a proinflammatory MCP-1-related pathway.
Waeckel
Ludovic
L
Cardiovascular Research Center, INSERM U689, Université Paris 7, Paris, France.
Bignon
Jérôme
J
Liu
Jian-Miao
JM
Markovits
Delphine
D
Ebrahimian
Téni G
TG
Vilar
José
J
Mees
Barend
B
Blanc-Brude
Olivier
O
Barateau
Véronique
V
Le Ricousse-Roussanne
Sophie
S
Duriez
Micheline
M
Tobelem
Gérard
G
Wdzieczak-Bakala
Joanna
J
Lévy
Bernard I
BI
Silvestre
Jean-Sébastien
JS
D000818:Animals; D001854:Bone Marrow Cells / Q000473:pathology; D002454:Cell Differentiation; D002461:Cell Line, Transformed; D018932:Chemokine CCL2 / Q000172:deficiency / Q000502:physiology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology; D005263:Femoral Artery / Q000473:pathology; D006614:Hindlimb / Q000098:blood supply*; D007511:Ischemia / Q000188:drug therapy* / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D009842:Oligopeptides / Q000008:administration & dosage*; D015398:Signal Transduction / Q000187:drug effects
D018932:Chemokine CCL2; D009842:Oligopeptides; C058504:goralatide