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PlGF, thought to be redundant in function compared to VEGF-A, is associated with increased blood\u2013brain barrier permeability, although the exact mechanism remains unknown. We examined the effects of a functional knockout of PlGF in mice (PlGF-DE-Ki) on vascular injury resulting from dietary induction of hyperhomocysteinemia (HHcy), a model of spontaneous cerebral small vessel disease. Immunohistochemistry showed reductions in vascular density and reductions in astrocytic endfoot coverage and pericytes in PlGF-DE-Ki mice compared to wild-type mice, regardless of diet. Vascular leakage assessed by multiphoton microscopy showed minimal changes, although PlGF-DE-Ki showed increased microhemorrhages compared to wild-type mice with Prussian blue staining. PlGF-DE-Ki mice also showed increased neuroinflammation by greater numbers of GFAP-positive cells and transcriptional upregulation of the complement pathway. Introduction of HHcy further increased the number of cerebral microhemorrhages and the number of microglia in the hippocampus. 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