Placental Growth Factor (PGF) deficiency is associated with impaired cerebral vascular development in mice

Abstract

Placental growth factor (PGF) rises in maternal plasma over normal human and mouse pregnancy but is low in many women with the acute onset hypertensive syndrome preeclampsia (PE). Pregnancies in Pgf-/- mice seem normal but cerebral vascular defects are present in Pgf-/- adult mice. Here, temporal–spatial expression of PGF is mapped in normal fetal mouse brains and cerebral vasculature development is compared between normal and congenic Pgf-/- fetuses to assess the actions of PGF during cerebrovascular development. Pgf/PGF, Vegfa/VEGF, Vegf receptor (Vegfr)1 and Vegfr2 expression were examined in the brains of embryonic day (E)12.5, 14.5, 16.5 and 18.5 C57BL/6 (B6) mice using quantitative PCR and immunofluorescence histology. Pgf/PGF and Vegfr1 are highly expressed in E12.5-14.5 forebrain relative to VEGF and Vegfr2. Vegfa/VEGF is relatively more abundant in hindbrain. PGF and VEGF expression were similar in midbrain. Delayed hindbrain vascularization was seen at E10.5 and 11.5 in Pgf-/-. At E14.5, Pgf-/- circle of Willis showed unilateral hypoplasia and fewer collateral vessels, defects that persisted postnatally. Functionally, Pgf-/- mice experienced cerebral ischemia after left common carotid arterial occlusion while B6 did not. These results highlight the importance of fetal PGF in cerebral vascularization and in resistance to stroke. PGF is dynamically expressed in fetal mouse brain, particularly forebrain and is essential for normal cerebrovascular development. These studies provoke the question of whether human cerebral vascular maldevelopment occurs in fetuses who experience a preeclamptic gestation, a population reported at elevated risk for stroke and cognitive impairment.