Increased vascular permeability is an early event characteristic of tissue
ischemia and angiogenesis. Although
VEGF family members are potent promoters of endothelial permeability the role of placental
growth factor (PlGF) is hotly debated. Here we investigated PlGF
isoforms 1 and 2 and present in vitro and in vivo evidence that PlGF-1, but not PlGF-2, can inhibit
VEGF-induced permeability but only during a critical window post-
VEGF exposure. PlGF-1 promotes
VE-cadherin expression via the trans-activating Sp1 and Sp3 interaction with the
VE-cadherin promoter and subsequently stabilizes transendothelial junctions, but only after activation of endothelial cells by
VEGF. PlGF-1 regulates vascular permeability associated with the rapid localization of
VE-cadherin to the plasma membrane and dephosphorylation of
tyrosine residues that precedes changes observed in
claudin 5 tyrosine phosphorylation and membrane localization. The critical window during which PlGF-1 exerts its effect on
VEGF-induced permeability highlights the importance of the translational significance of this work in that PLGF-1 likely serves as an endogenous anti-permeability factor whose effectiveness is limited to a precise time point following
vascular injury. Clinical approaches that would pattern nature's approach would thus limit treatments to precise intervals following injury and bring attention to use of agents only during therapeutic windows.