Plasminogen deficiency causes reduced angiogenesis and behavioral recovery after stroke in mice
Jinghuan Fang, Michael Chopp, Hongqi Xin, Zhang Li, Fengjie Wang, William Golembieski, Zheng Gang Zhang, Li He, Zhongwu Liu
Abstract
Plasminogen is involved in the process of angiogenesis; however, the underlying mechanism is unclear. Here, we investigated the potential contribution of plasmin/plasminogen in mediating angiogenesis and thereby contributing to functional recovery post-stroke. Wild-type plasminogen naive (Plg +/+ ) mice and plasminogen knockout (Plg −/− ) mice were subjected to unilateral permanent middle cerebral artery occlusion (MCAo). Blood vessels were labeled with FITC-dextran. Functional outcomes, and cerebral vessel density were compared between Plg +/+ and Plg −/− mice at different time points after stroke. We found that Plg −/− mice exhibited significantly reduced functional recovery, associated with significantly decreased vessel density in the peri-infarct area in the ipsilesional cortex compared with Plg +/+ mice. In vitro, cerebral endothelial cells harvested from Plg −/− mice exhibited significantly reduced angiogenesis assessed using tube formation assay, and migration, as evaluated using Scratch assays, compared to endothelial cells harvested from Plg +/+ mice. In addition, using Western blots, expression of thrombospondin (TSP)-1 and TSP-2 were increased after MCAo in the Plg −/− group compared to Plg +/+ mice, especially in the ipsilesional side of brain. Taken together, our data suggest that plasmin/plasminogen down-regulates the expression level of TSP-1 and TSP-2, and thereby promotes angiogenesis in the peri-ischemic brain tissue, which contributes to functional recovery after ischemic stroke.