Deficiency in Plasminogen Cause Decreased Vascularity in Sold Tissue Organs and Bone

A sufficient vascular supply is critical for proper physiologic function of solid-tissue organs and bone. Tissue vascularity is mediated concomitantly through vascular patency and angiogenesis. Recently, numerous studies have associated plasminogen, the key fibrinolytic protease of the coagulation system, with maintaining vascular patency by preventing fibrin accumulation with in the vasculature. Additionally, plasminogen may also have a direct role in angiogenesis as it has been shown in vitro that inhibitors of plasmin(ogen) suppress formation of capillary structures from normal endothelial cells and cells cultured from plasmin(ogen) deficient mice have reduced capillary sprouting in response to the angiogenic stimulator VEGF-A. Therefore, we hypothesized that plasminogen is essential for developing and maintaining vascularity in solid-tissue organs and revascularization of bone fracture calluses. To determine if there was a discernable difference in vivo between the vascular supply of plasminogen deficient (plg^−/−) and wild type mice we performed microfil profusion studies visualized using a Sanco 40 μCT. We determined that plg^−/− mice have a diminished renal and hepatic vascularity compared to wild type mice at 3 and 20 weeks of age (Figure 1). Further, we show that plg^−/− mice fail to develop a blood supply at the fracture site by week 2 post-fracture whereas the control mice exhibit a highly neovascularized capillary system (Figure 2). Plg ^−/− mice also fail to develop a mineralized callus around a two week old fracture site demonstrating a role for plasmin(ogen) in osteoblast minimization. These findings demonstrate that disruption of the fibrinolytic system's main proteolytic enzyme plasmin results in decreased vascularity of solid-tissue organs and revascularization of bone fracture calluses. While the role of plasmin(ogen) in vascularity is clear, further studies are warranted to elucidate its mechanisms of action. Studies investigating plasmin(ogen)'s role in vascularity may have importance in variety of biologic conditions and pathologies. For example, aging, diabetes and smoking, all of which are known to incur an acquired deficiency or dysfunction of fibrinolysis lead to complications of vascularity (cardiovascular disease) and are also associated with pathologic bone disease (osteoporosis and poor fracture healing). These data indicate that plasmin(ogen) and its biologic targets may provide future novel therapeutic targets for treatment of pathologies involving impaired vascularization.