title: Placenta growth factor-1 exerts time-dependent stabilization of adherens junctions following VEGF-induced vascular permeability.
abstract: 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.
authors.affiliation: Department of Anatomy and Cell Biology, University of Florida, Gainesville, Florida, United States of America.
authors.forename: Jun
authors.initials: J
authors.lastname: Cai
authors.forename: Lin
authors.initials: L
authors.lastname: Wu
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Qi
authors.forename: Lynn
authors.initials: L
authors.lastname: Shaw
authors.forename: Sergio
authors.initials: S
authors.lastname: Li Calzi
authors.forename: Sergio
authors.initials: S
authors.lastname: Caballero
authors.forename: Wen G
authors.initials: WG
authors.lastname: Jiang
authors.forename: Stanley A
authors.initials: SA
authors.lastname: Vinores
authors.forename: David
authors.initials: D
authors.lastname: Antonetti
authors.forename: Asif
authors.initials: A
authors.lastname: Ahmed
authors.forename: Maria B
authors.initials: MB
authors.lastname: Grant
authors.forename: Michael E
authors.initials: ME
authors.lastname: Boulton
mesh_terms: D022005:Adherens Junctions / Q000187:drug effects* / Q000378:metabolism*; D000818:Animals; D015703:Antigens, CD / Q000235:genetics; D001483:Base Sequence; D015820:Cadherins / Q000235:genetics; D002199:Capillary Permeability / Q000187:drug effects*; D057167:Claudins / Q000378:metabolism; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D010766:Phosphorylation / Q000187:drug effects; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D016329:Sp1 Transcription Factor / Q000378:metabolism; D051705:Sp3 Transcription Factor / Q000378:metabolism; D019108:Tight Junctions / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D015533:Transcriptional Activation / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D057167:Claudins; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins; D016329:Sp1 Transcription Factor; D051705:Sp3 Transcription Factor; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D000099152:Cadherin 5; C000608036:PGF protein, human; C000608037:Pgf protein, mouse