Full functional knockout of placental growth factor primes the mouse neurovasculature for inflammation and injury

The MarkVCID consortium investigating biomarkers for vascular contributions to cognitive impairment and dementia (VCID) found placental growth factor (PlGF) correlated with white matter hyperintensities and cognitive impairment. PlGF, thought to be redundant in function compared to VEGF-A, is associated with increased blood-brain 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. These results indicate that lifetime knockdown of PlGF functionality increases susceptibility to vascular injury.