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

Pang, Vincent; Bates, David O.; Leach, Lopa

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 (p0.05) or PlGF (p>0.05) did not. Moreover, VEGF-A165b (100 ng/ml; p0.05) 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.

Citation

Pang, V., Bates, D. O., & Leach, L. (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, 131(23), 2763-2775. https://doi.org/10.1042/CS20171252

• Journal Article Type: Article
• Acceptance Date: Oct 19, 2017
• Online Publication Date: Nov 23, 2017
• Publication Date: Nov 23, 2017
• Deposit Date: Nov 1, 2017
• Publicly Available Date: Aug 15, 2018
• Journal: Clinical Science
• Print ISSN: 0143-5221
• Electronic ISSN: 1470-8736
• Publisher: Portland Press
• Peer Reviewed: Peer Reviewed
• Volume: 131
• Issue: 23
• Pages: 2763-2775
• DOI: https://doi.org/10.1042/CS20171252
• Keywords: VEGF, permeability, placenta, VE-cadherin
• Public URL: https://nottingham-repository.worktribe.com/output/888824
• Publisher URL: http://www.clinsci.org/content/131/23/2763
• Contract Date: Nov 1, 2017