Regulation of human feto-placental endothelial barrier integrity by vascular endothelial growth factors: competitive interplay between VEGF-A165a, VEGF-A165b, PIGF and VE-cadherin

Pamg, Vincent and Bates, David O. and Leach, Lopa (2017) Regulation of human feto-placental endothelial barrier integrity by vascular endothelial growth factors: competitive interplay between VEGF-A165a, VEGF-A165b, PIGF and VE-cadherin. Clinical Science . ISSN 1470-8736 (In Press)

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Abstract

The human placenta nourishes and protects the developing fetus whilst influencing maternal physiology for fetal advantage. It expresses several members of the VEGF family including the pro-angiogenic/pro-permeability VEGF-A165a isoform, the anti-angiogenic VEGF-A165b, placental growth factor (PIGF) and their receptors, VEGFR1 and VEGFR2. Alterations in the ratio of these factors during gestation and in complicated pregnancies have been reported; however the impact of this on feto-placental endothelial barrier integrity is unknown. This study investigated the interplay of these factors on junctional occupancy of VE-cadherin and macromolecular leakage in human endothelial monolayers and the perfused placental microvascular bed. Whilst VEGF-A165a (50 ng/ml) increased endothelial monolayer albumin permeability (p<0.0001), equimolar concentrations of VEGF-A165b (p>0.05) or PlGF (p>0.05) did not. Moreover, VEGF-A165b (100 ng/ml; p<0.001) but not PlGF (100 ng/ml; p>0.05) inhibited VEGF-A165a-induced permeability when added singly. PlGF abolished the VEGF-A165b-induced reduction of VEGF-A165a mediated permeability (p>0.05); PlGF was found to compete with VEGF-A165b for binding to Flt-1 at equimolar affinity. Junctional occupancy of VE-cadherin matched alterations in permeability. In the perfused microvascular bed, VEGF-A165b did not induce microvascular leakage but inhibited and reversed VEGF-A165a-induced loss of junctional VE-cadherin and tracer leakage. These results indicate that the anti-angiogenic VEGF-A165b isoform does not increase permeability in human placental microvessels or HUVEC primary cells and can interrupt VEGF-A165a-induced permeability. Moreover, the interplay of these isoforms with PIGF (and s-flt1) suggests that the ratio of these three factors may be important in determining the placental and endothelial barrier in normal and complicated pregnancies.

Item Type: Article
Keywords: VEGF, permeability, placenta, VE-cadherin
Schools/Departments: University of Nottingham, UK > Faculty of Medicine and Health Sciences > School of Medicine > Division of Cancer and Stem Cells
University of Nottingham, UK > Faculty of Medicine and Health Sciences > School of Life Sciences
Identification Number: 10.1042/CS20171252
Depositing User: Leach, Lopa
Date Deposited: 01 Nov 2017 11:02
Last Modified: 01 Nov 2017 11:04
URI: http://eprints.nottingham.ac.uk/id/eprint/47721

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