Yongjie Li1,2, Qian Gao1,2, Xin Shu1,2, Lamei Xiao1,2, Yan Yang1,2, Ningbo Pang1,2, Yulin Luo1,2, Jing He1,2, Liping Zhang1,2, Jianbo Wu1,2. 1. Key Laboratory of Medical Electrophysiology of Ministry of Education, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Drug Discovery Research Center, Southwest Medical University, Luzhou, China. 2. Laboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China.
Abstract
Background: αVβ3 integrin has been implicated in the physiological processes and pathophysiology of important angiogenesis-related disorders; however, the preclinical and clinical data on integrin αVβ3 antagonists have not demonstrated improved outcomes. Our goal was to test the hypothesis that inhibition of αVβ3 integrin improves blood flow in a mouse hindlimb ischemia model. Methods: In this study, we examined the effect of cilengitide, an αVβ3/αVβ5 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 αVβ3 integrin in modulating ischemia-induced angiogenesis, possibly through effects on macrophage infiltration and polarization, and revealed αVβ3 integrin inhibition to be a promising therapeutic strategy for peripheral artery disease.
Background: αVβ3 integrin has been implicated in the physiological processes and pathophysiology of important angiogenesis-related disorders; however, the preclinical and clinical data on integrin αVβ3 antagonists have not demonstrated improved outcomes. Our goal was to test the hypothesis that inhibition of αVβ3 integrin improves blood flow in a mouse hindlimb ischemia model. Methods: In this study, we examined the effect of cilengitide, an αVβ3/αVβ5 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 αVβ3 integrin in modulating ischemia-induced angiogenesis, possibly through effects on macrophage infiltration and polarization, and revealed αVβ3 integrin inhibition to be a promising therapeutic strategy for peripheral artery disease.
Authors: Ping-Pui Wong; Fevzi Demircioglu; Essam Ghazaly; Wasfi Alrawashdeh; Michael R L Stratford; Cheryl L Scudamore; Biancastella Cereser; Tatjana Crnogorac-Jurcevic; Stuart McDonald; George Elia; Thorsten Hagemann; Hemant M Kocher; Kairbaan M Hodivala-Dilke Journal: Cancer Cell Date: 2015-01-12 Impact factor: 31.743
Authors: Jason U Tilan; Lindsay M Everhart; Ken Abe; Lydia Kuo-Bonde; Dan Chalothorn; Joanna Kitlinska; Mary Susan Burnett; Stephen E Epstein; James E Faber; Zofia Zukowska Journal: FASEB J Date: 2013-03-01 Impact factor: 5.191