New functions of the fibrinolytic system in bone marrow cell-derived angiogenesis

Abstract

Angiogenesis is a process by which new blood vessels form from preexisting vasculature. This process includes differentiation of angioblasts into endothelial cells with the help of secreted angiogenic factors released from cells such as bone marrow (BM)-derived cells. The fibrinolytic factor plasmin, which is a serine protease, has been shown to promote endothelial cell migration either directly, by degrading matrix proteins such as fibrin, or indirectly, by converting matrix-bound angiogenic growth factors into a soluble form. Plasmin can also activate other pericellular proteases such as matrix metalloproteinases (MMPs). Recent studies indicate that plasmin can additionally alter cellular adhesion and migration. We showed that factors of the fibrinolytic pathway can recruit BM-derived hematopoietic cells into ischemic/hypoxic tissues by altering the activation status of MMPs. These BM-derived cells can function as accessory cells that promote angiogenesis by releasing angiogenic signals. This review will discuss recent data regarding the role of the fibrinolytic system in controlling myeloid cell-driven angiogenesis. We propose that plasmin/plasminogen may be a potential target not only for development of effective angiogenic therapeutic strategies for the treatment of cancer, but also for development of strategies to promote ischemic tissue regeneration.

Pleiotrophin-induced endothelial cell migration is regulated by xanthine oxidase-mediated generation of reactive oxygen species

“…It is not known whether this is the reason for the decrease in cell migration caused by PTN in the presence of AEBSF, but it may be a possibility since PTN has been shown to enhance plasminogen activator activity in bovine aortic endothelial cells (Kojima et al, 1995). Considering the basic role of plasmin in endothelial cell migration (Heissig et al, 2012), it could be hypothesized that PTN exerts its stimulatory effect on cell migration by activating serine proteases.…”

Cell Surface Remodeling by Plasmin: A New Function for an Old Enzyme

“…Mechanistically, plasmin activity was linked to the activation of MMP-9 and MMP-9-induced release of Kit ligand, the factor that earlier was shown to be obligatory for immobilization of hematopoietic stem/progenitor cells (HSPCs) from bone marrow in response to myelosuppression [121]. The specific mechanisms whereby the plasmin fibrinolytic and MMP pathways control each other and cooperatively regulate hematopoiesis, hematopoietic regeneration, and angiogenesis driven by myeloid cells are described in detail in reviews by Heissig and coauthors [122, 123]. An important clinical implication of functional activation of MMP-9 by plasmin was recently demonstrated by inhibitory effects of the active-site-directed inhibitor of plasmin, YO-2, on MMP-9-dependent growth of T-cell lymphoma and recruitment of tumor-promoting myeloid cells to the sites of tumor development [124].…”

Fibrinolytic crosstalk with endothelial cells expands murine mesenchymal stromal cells

“…Activation of plasmin or MMPs cannot only accelerate local ECM degradation but can also lead to the activation/inactivation of chemo-/cytokines, receptors, and other proteases. 19,20 Mice deficient in membrane type 1 MMP show a decrease in the number of CD45 …”