PDGF-D is de novo expressed after stroke and contributes to neurovascular protection by rescuing the function of pericytes

Abstract Ischemic stroke induces an angiogenic response at the lesion site to improve tissue vascularization, as an attempt to promote repair. Brain pericytes, which are critically involved in regulating neurovascular functions, potently respond to stroke stressors, varying from death to detachment. Platelet-derived growth factor (PDGF) receptor (PDGFR)β plays a central role in pericyte survival, proliferation, migration, and recruitment to endothelial cells. The role of PDGF-D, a recently identified ligand that specifically binds and activates PDGFRβ, in ischemic stroke pathobiology, remains unexplored. Herein, we show that PDGF-D is transiently induced in vascular structures at the lesion site in experimental ischemic stroke. Attenuation of PDGF-D subacute induction using siRNA exacerbates injury and impairs vascular integrity. Enhancing PDGF-D subacute bioavailability via the intranasal delivery of an active form, attenuates neuronal loss and improves neurological recovery. PDGF-D stimulates the formation of a stable vasculature, improves brain perfusion, and rescues pericyte coverage, associated with an increased expression of insulin growth factor (IGF)1, a vascular protective factor. PDGF-D stimulation enhances the survival of human brain pericytes exposed to ischemic-like conditions in vitro by increasing the expression of B-cell lymphoma (BCL)2, while reducing the expression of neurogenic locus notch homolog (NOTCH)3, involved in pathological fibrosis. PDGF-D stimulation enhances the migratory properties of pericytes exposed to ischemic-like conditions, required for vascular coverage, and induces the release of factors involved in fine-tuning vascular remodeling. Our study provides new insights into the role of PDGF-D in preserving neurovascular functions after stroke by rescuing the function of pericytes, outlining its therapeutic potential.