Abstract 9998: Mechanisms Underlying the Impairment of Ischemia-Induced Neovascularization in Cathepsin K-Deficient Mic
Background: Cysteine protease cathepsins (Cats) have been implicated in the process of neovascularization. However, the exact roles of individual Cat proteins in vessel formation are poorly understood. Methods and Results: To study the putative role of cathepsin K (CatK) in ischemia-induced neovascularization, a hindlimb ischemia model was applied to CatK+/+ and CatK-/- mice. Serial laser Doppler blood-flow analysis revealed that the recovery of the ischemic/normal blood-flow ratio in CatK-/- young and old mice remained impaired throughout the follow-up period. At day 28, anti-L-lectin immunohistochemical staining revealed less developed capillary formation in both old and young CatK-/- mice compared with age-matched CatK+/+ mice. CatK deficiency reduced macrophage infiltration in the ischemic muscle. An aortic-ring culture assay showed a markedly impaired angiogenic response in CatK-/- mice. Aorta-derived endothelial cells and bone marrow-derived endothelial progenitor cell (EPC)-like c-Kit+ cells from CatK-/- showed marked impairment of invasive and proliferative abilities. On day 7, plasma and ischemic tissues of CatK+/+ showed reduce vascular endothelial growth factor protein and stromal cell derived factor-1. Flow cytometry showed that the numbers of EPC-like CD31+/c-Kit+ cells in peripheral blood markedly decreased in CatK-/- mice. Transplantation of bone marrow-derived mononuclear cells from CatK+/+ mice restored neovascularization in CatK-/- young mice.
Conclusions: These data suggest that CatK deficiency impairs ischemia induced neovascularization through a reduction of endothelial cell and EPC functions and EPC mobilization.
- © 2012 by American Heart Association, Inc.