Vascular endothelial growth factor signaling implicated in neuroprotective effects of placental growth factor in an in vitro ischemic model

Abstract

Placental growth factor (PlGF) is involved in the angiopoiesis of the placental chorion and the maintenance of the placenta. Some additional roles of PlGF in other tissues have recently been described. Relatively little is known about PlGF expression in the CNS and the involvement of PlGF in cerebral ischemia injury. We examined the expression of PlGF in cerebral ischemia, utilizing a permanent middle cerebral artery occlusion (MCAO) model in the rat. PlGF expression and release from brain microvascular endothelial cells (BMECs) in response to oxygen and glucose deprivation (OGD) were examined in primary culture. To elucidate the effects of PlGF in cerebral ischemic injury, we investigated the effects of varying concentrations of PlGF upon neurons in an in vitro model of OGD. The effects of PlGF upon neuronal vascular endothelial growth factor receptor-1 (VEGFR-1) and vascular endothelial growth factor receptor-2 (VEGFR-2) expression were examined. We detected PlGF immunoreactivity mainly in the microvessels and interstitum of rat brain cortex after cerebral ischemic injury. In primary BMECs, PlGF expression and release were significantly higher under OGD conditions in culture. In primary cultures of rat cortical neurons, PlGF administration reduced cell death in an in vitro model of OGD. VEGFR-1 and VEGFR-2 were expressed in primary cortical neurons as measured by Western blotting. VEGFR-2 expression in primary neurons was significantly higher following PlGF administration. These data demonstrate that VEGFR-2 signaling may play a role in PlGF-mediated neuroprotection, and that PlGF may be a promising target for therapeutic intervention in ischemic injury.