Matrix Metalloproteinase-9 Is Essential for Ischemia-Induced Neovascularization by Modulating Bone Marrow–Derived Endothelial Progenitor Cells

Abstract

Objective-Both matrix metalloproteinases (MMPs) and endothelial progenitor cells (EPCs) have been implicated in the process of neovascularization. Here we show that the impaired neovascularization in mice lacking MMP-9 is related to a defect in EPC functions in vasculogenesis. Methods and Results-Hindlimb ischemia surgery was conducted in MMP-9 Ϫ/Ϫ mice and wild-type (MMP-9 ϩ/ϩ ) mice. Blood flow recovery was markedly impaired in MMP-9 Ϫ/Ϫ mice when compared with that in wild-type mice as determined by laser Doppler imaging. Flow cytometry demonstrated that the number of EPC-like cells (Sca-1 ϩ /Flk-1 ϩ ) in peripheral blood increased in wild-type mice after hindlimb ischemia surgery and exogenous vascular endothelial growth factor stimulation, but not in MMP-9 Ϫ/Ϫ mice. Plasma levels and bone marrow concentrations of soluble Kit-ligand (sKitL) were significantly elevated in wild-type mice in response to tissue ischemia, but not in MMP-9 Ϫ/Ϫ mice. C-kit positive bone marrow cells of MMP-9 Ϫ/Ϫ mice have attenuated adhesion and migration than those isolated from wild-type mice. In in vitro studies, incubation with selective MMP-9 inhibitor suppressed the colony formation, migration, and tube formation capacities of EPC. Transplantation of bone marrow cells from wild-type mice restored collateral flow formation in MMP-9 Ϫ/Ϫ mice. Conclusions-These findings suggest that MMP-9 deficiency impairs ischemia-induced neovascularization, and these effects may occur through a reduction in releasing the stem cell-active cytokine, and EPC mobilization, migration, and vasculogenesis functions.

Interleukin-10 overexpression improves the function of endothelial progenitor cells stimulated with TNF-α through the activation of the STAT3 signaling pathway

“…In addition, MMPs can modify non-ECM molecules, such as VEGFR, to affect EC vitality and behavior (31). In addition, deficiency of MMP-9 attenuates ischemia-induced neovascularization through an impairment of bone marrow-derived EPC adhesion, migration and proangiogenic functions (32). Therefore, the present result suggests that IL-10 promotes the EPC migration, adhesion and tube formation by increasing MMP-9 and VEGF expression, and activating the STAT3 signaling pathway.…”

Number of Endothelial Progenitor Cells in Peripheral Artery Disease as a Marker of Severity and Association with Pentraxin-3, Malondialdehyde-Modified Low-Density Lipoprotein and Membrane Type-1 Matrix Metalloproteinase

“…Matrix metalloproteinase (MMP) plays a key role in EPC mobilization and angiogenesis 16) . MT1-MMP, a transmembrane type protease, has been recognized as an important regulator in EPC mobilization from bone marrow and angiogenesis 17) .…”

“…Oxidized low-density lipoprotein decreased the survival of EPCs and impaired their function through decreased endothelial nitric oxide synthetase expression 15) . EPC mobilization occurs also through matrix metalloproteinase-mediated mechanisms [16][17][18] . Matrix metalloproteinase species activate local protease activity and weaken stromal cell-EPC interactions in the bone marrow.…”

Identyfikacja i znaczenie krążących endotelialnych komórek progenitorowych u chorych na raka wątrobowokomórkowego

“…Czynnikiem wyzwalającym angiogenezę jest postępujące w miarę wzrostu guza niedotlenienie tkanki i aktywność cytokin nowotworowych [1,11,22,23]. Szczególną rolę w tym procesie przypisuje się czynnikowi wzrostu śródbłonka naczyniowego (VEGF), którego działanie jest katalizatorem przemian i uwalniania ze szpiku kostnego komórek progenitorowych, w wyniku czego ich liczebność w krążeniu obwodowym wzrasta.…”