Bone marrow-derived CCR5-expressing macrophages promote venous thrombus resolution by up-regulating plasminogen activators and VEGF

BackgroundDeep vein thrombosis (DVT) is a common peripheral vascular disease arising from endothelial damage and can frequently result in pulmonary embolism. C-C chemokine receptor 5 (CCR5) is essentially involved in skin wound healing and pulmonary fibrosis, but the role of CCR5 still remains elusive. MethodsDeep vein thrombus was induced by the ligation of the inferior vena cava (IVC) in wild-type (WT) mice and Ccr5-/- mice, and thrombi were collected over time and various analyzes were performed. ResultsAfter ligation of the IVC in WT mice, a venous thrombus developed progressively until 5 days, and then resolved. Concomitantly, IVC ligation enhanced intrathrombotic gene and protein expression of Ccr5 and its ligand, Ccl5, and both were expressed mainly by intrathrombotic macrophages. The same treatment of Ccr5-/- mice resulted in significantly greater thrombus mass than WT mice. Moreover, the administration of a specific CCR5 inhibitor to WT mice recapitulated similar phenotypes as Ccr5-/- mice while that of CCL5 caused the opposite phenotypes. In Ccr5-/- mice, the production of intrathrombotic vascular endothelial growth factor (VEGF), tissue plasminogen activator (tPA), and urokinase-type plasminogen activator (uPA) from macrophages was significantly reduced and intrathrombotic recanalization was also suppressed compared to WT mice. Moreover, CCL5 enhanced Vegf, Plat, and Plau gene expression in WT-derived peritoneal macrophages by activating the ERK MAPK signaling pathway in vitro. ConclusionsCCR5-deficient mice exhibited reduced expression of Vegf, Plat, and Plau, with concomitant attenuated neovascularization and reduced thrombus resolution. the Thus, the augmentation of the CCL5-CCR5 axis may be effective for DVT treatment by enhancing thrombolysis.