Urokinase-type plasminogen activator (uPA) and its receptor (uPAR) promote neurorepair in the ischemic brain.

Abstract

Despite the fact that ischemic stroke has been considered a leading cause of mortality in the world, recent advances in our understanding of the pathophysiological mechanisms underlying the ischemic injury and the treatment of acute ischemic stroke patients have led to a sharp decrease in the number of stroke deaths. However, this decrease in stroke mortality has also led to an increase in the number of patients that survive the acute ischemic injury with different degrees of disability. Unfortunately, to this date we do not have an effective therapeutic strategy to promote neurological recovery in these growing population of stroke survivors. Cerebral ischemia not only causes the destruction of a large number of axons and synapses but also activates endogenous mechanisms that promote the recovery of those neurons that survive its harmful effects. Here we review experimental evidence indicating that one of these mechanisms of repair is the binding of the serine proteinase urokinase-type plasminogen activator (uPA) to its receptor (uPAR) in the growth cones of injured axons. Indeed, the binding of uPA to uPAR in the periphery of growth cones of injured axons induces the recruitment of β1-integrin to the plasma membrane, β1-integrin-mediated activation of the small Rho GTPase Rac1, and Rac1-induced axonal regeneration. Furthermore, we found that this process is modulated by the low density lipoprotein receptor-related protein (LRP1). The data reviewed here indicate that the uPA-uPAR-LRP1 system is a potential target for the development of therapeutic strategies to promote neurological recovery in acute ischemic stroke patients.