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COVID-19 is a respiratory disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). COVID-19 pathogenesis causes vascular-mediated neurological disorders via still elusive mechanisms. SARS-CoV-2 infects host cells by binding to angiotensin-converting enzyme 2 (ACE2), a transmembrane receptor that recognizes the viral spike (S) protein. Brain pericytes were recently shown to express ACE2 at the neurovascular interface, outlining their possible implication in microvasculature injury in COVID-19. Yet, pericyte responses to SARS-CoV-2 is still to be fully elucidated. Using cell-based assays, we report that ACE2 expression in human brain vascular pericytes is highly dynamic and is increased upon S protein stimulation. Pericytes exposed to S protein underwent profound phenotypic changes translated by increased expression of contractile and myofibrogenic proteins, namely α-smooth muscle actin (α-SMA), fibronectin, collagen I, and neurogenic locus notch homolog protein-3 (NOTCH3). These changes were associated to an altered intracellular calcium (Ca2+) dynamic. Furthermore, S protein induced lipid peroxidation, oxidative and nitrosative stress in pericytes as well as triggered an immune reaction translated by activation of nuclear factor-kappa-B (NF-κB) signalling pathway, which was potentiated by hypoxia, a condition associated to vascular comorbidities, which exacerbate COVID-19 pathogenesis. S protein exposure combined to hypoxia enhanced the production of pro-inflammatory cytokines involved in immune cell activation and trafficking, namely interleukin-8 (IL-8), IL-18, macrophage migration inhibitory factor (MIF), and stromal cell-derived factor-1 (SDF-1). Finally, we found that S protein could reach the mouse brain via the intranasal route and that reactive ACE2-expressing pericytes are recruited to the damaged tissue undergoing fibrotic scarring in a mouse model of cerebral multifocal micro-occlusions, a main reported vascular-mediated neurological condition associated to COVID-19. Our data demonstrate that the released S protein is sufficient to mediate pericyte immunoreactivity, which may contribute to microvasculature injury in absence of a productive viral infection. Our study provides a better understanding for the possible mechanisms underlying cerebrovascular disorders in COVID-19, paving the way to develop new therapeutic interventions.

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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.