Schematic diagram showing the various molecules involved in the proangiogenic effect of PAI-1 inhibition. Under ischemic conditions, the local balance between the fibrinolytic factor tPA and one of its endogenous inhibitors, PAI-1, is shifted toward a profibrinolytic state with a local increase in tPA. Ischemia systemically results in a profibrinolytic state, a process dependent on endogenous tPA. Pharmacologic PAI-1 inhibition during ischemic recovery improved tissue regeneration due to an expansion of circulating and tissue-resident Gr-1⁺ neutrophils coexpressing VEGF-A, FGF-2, and TIMP-1–free MMP-9, and to increased release of the angiogenic factor VEGF-A, the hematopoietic growth factor KitL, and G-CSF. Ab neutralization and genetic-knockout studies indicated that both the improved tissue regeneration and the increase in both circulating and ischemic tissue-resident Gr-1⁺ neutrophils were dependent on the activation of tPA and MMP-9 and on VEGF-A and FGF-2.