The Role of Heparan Sulfate and Neuropilin 2 in VEGFA Signaling in Human Endothelial Tip Cells and Non-Tip Cells during Angiogenesis In Vitro.

Details

Serval ID
serval:BIB_F1688DEB3369
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
The Role of Heparan Sulfate and Neuropilin 2 in VEGFA Signaling in Human Endothelial Tip Cells and Non-Tip Cells during Angiogenesis In Vitro.
Journal
Cells
Author(s)
Dallinga M.G., Habani Y.I., Schimmel AWM, Dallinga-Thie G.M., van Noorden CJF, Klaassen I., Schlingemann R.O.
ISSN
2073-4409 (Electronic)
ISSN-L
2073-4409
Publication state
Published
Issued date
16/04/2021
Peer-reviewed
Oui
Volume
10
Number
4
Pages
926
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: epublish
Abstract
During angiogenesis, vascular endothelial growth factor A (VEGFA) regulates endothelial cell (EC) survival, tip cell formation, and stalk cell proliferation via VEGF receptor 2 (VEGFR2). VEGFR2 can interact with VEGFR2 co-receptors such as heparan sulfate proteoglycans (HSPGs) and neuropilin 2 (NRP2), but the exact roles of these co-receptors, or of sulfatase 2 (SULF2), an enzyme that removes sulfate groups from HSPGs and inhibits HSPG-mediated uptake of very low density lipoprotein (VLDL), in angiogenesis and tip cell biology are unknown. In the present study, we investigated whether the modulation of binding of VEGFA to VEGFR2 by knockdown of SULF2 or NRP2 affects sprouting angiogenesis, tip cell formation, proliferation of non-tip cells, and EC survival, or uptake of VLDL. To this end, we employed VEGFA splice variant 121, which lacks an HSPG binding domain, and VEGFA splice variant 165, which does have this domain, in in vitro models of angiogenic tip cells and vascular sprouting. We conclude that VEGFA <sub>165</sub> and VEGFA <sub>121</sub> have similar inducing effects on tip cells and sprouting in vitro, and that the binding of VEGFA <sub>165</sub> to HSPGs in the extracellular matrix does not seem to play a role, as knockdown of SULF2 did not alter these effects. Co-binding of NRP2 appears to regulate VEGFA-VEGFR2-induced sprout initiation, but not tip cell formation. Finally, as the addition of VLDL increased sprout formation but not tip cell formation, and as VLDL uptake was limited to non-tip cells, our findings suggest that VLDL plays a role in sprout formation by providing biomass for stalk cell proliferation.
Keywords
Apoptosis, Heparitin Sulfate/metabolism, Human Umbilical Vein Endothelial Cells/metabolism, Humans, Lipoproteins, VLDL/metabolism, Neovascularization, Physiologic, Neuropilin-2/metabolism, Signal Transduction, Sulfatases/metabolism, Vascular Endothelial Growth Factor A/metabolism, Vascular Endothelial Growth Factor Receptor-2/metabolism, HSPG, NRP2, SULF2, VEGFA, angiogenesis, endothelial cells, tip cells
Pubmed
Web of science
Open Access
Yes
Create date
07/05/2021 18:08
Last modification date
30/12/2023 8:07
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