Antagonizing ?v?3 Integrin Improves Ischemia-Mediated Vascular Normalization and Blood Perfusion by Altering Macrophages.

ABSTRACT: Background: ?V?3 integrin has been implicated in the physiological processes and pathophysiology of important angiogenesis-related disorders; however, the preclinical and clinical data on integrin ?V?3 antagonists have not demonstrated improved outcomes. Our goal was to test the hypothesis that inhibition of ?V?3 integrin improves blood flow in a mouse hindlimb ischemia model. Methods: In this study, we examined the effect of cilengitide, an ?V?3/?V?5 integrin-specific RGD-mimetic cyclic peptide, on blood perfusion and angiogenesis after hindlimb ischemia. Blood flow was measured using Laser Doppler Scanner. Vascular density, and macrophages infiltration were examined by immunofluorescence. Macrophage polarization was measured by quantitative real time PCR. Results: We found that low-dose, not high-dose, cilengitide increased blood flow perfusion, capillary formation, and pericyte coverage, accompanied by an accumulation of macrophages and increased expression of the chemokine (C-C motif) ligand 2 (CCL2) in ischemic muscles. Macrophage depletion using clodronate liposomes resulted in a reduction in low-dose cilengitide-induced blood flow perfusion, macrophage accumulation, pericyte coverage, and CCL2 expression. Finally, in vitro assays showed that low-dose, not high-dose, cilengitide increased macrophage migration. Conclusion: These studies identified a novel role of the inhibition of ?V?3 integrin in modulating ischemia-induced angiogenesis, possibly through effects on macrophage infiltration and polarization, and revealed ?V?3 integrin inhibition to be a promising therapeutic strategy for peripheral artery disease.

SUBMITTER: Li Y 

PROVIDER: S-EPMC7944575 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature