VEGF-E Attenuates Injury After Ischemic Stroke by Promoting Reparative Revascularization

Abstract

The angiogenic response after stroke correlates with mild injury and an improved recovery. Stimulation of post-stroke angiogenesis using vascular endothelial growth factor (VEGF)-A is associated with an increased risk of vascular destabilization, leading to life-threatening complications. The non-mammalian VEGF-A homolog, VEGF-E, stimulates stable cutaneous vascularization and promotes wound healing. Herein, we posit that VEGF-E represents a potential mediator of reparative revascularization after ischemic stroke. C57BL6/J wildtype mice were subjected to experimental stroke, and VEGF-E or VEGF-A were intranasally delivered during the subacute phase. Our results indicate that VEGF-E improves neurological recovery and increases vascular density without compromising permeability, more efficiently than VEGF-A. We show that VEGF-E-mediated revascularization correlates with normal restoration of brain perfusion, whereas VEGF-A induces cerebral hyperperfusion, indicative of vascular dysfunction. Furthermore, VEGF-E reduces microvascular stalls, increases the density of angiogenic vasculature, and improves the interaction of brain endothelial cell with pericytes, which is critical for vascular stabilization. Using cell-based assays, we demonstrate that stimulation of brain endothelial cells with VEGF-E, but not with VEGF-A, increases the expression of platelet-derived growth factor (PDGF)-D, a potent ligand of PDGFRβ that plays critical roles in regulating the survival and functions of perivascular cells, including pericytes. These effects are associated with activation of extracellular signal-regulated kinase (ERK)1/2 and P38 mitogen-activated protein kinase (MAPK). Finally, we confirm that the secretome of VEGF-E-stimulated brain endothelial cells ameliorates pericyte migration required for vascular recruitment. Our study indicates that VEGF-E promotes a stable and functional revascularization after ischemic stroke, outlining its promises for therapeutic purposes.