VEGF dose regulates vascular stabilization through Semaphorin3A and the Neuropilin-1+ monocyte/TGF-β1 paracrine axis

EMBO Molecular Medicine
Elena GroppaAndrea Banfi

Abstract

VEGF is widely investigated for therapeutic angiogenesis, but while short-term delivery is desirable for safety, it is insufficient for new vessel persistence, jeopardizing efficacy. Here, we investigated whether and how VEGF dose regulates nascent vessel stabilization, to identify novel therapeutic targets. Monoclonal populations of transduced myoblasts were used to homogeneously express specific VEGF doses in SCID mouse muscles. VEGF was abrogated after 10 and 17 days by Aflibercept treatment. Vascular stabilization was fastest with low VEGF, but delayed or prevented by higher doses, without affecting pericyte coverage. Rather, VEGF dose-dependently inhibited endothelial Semaphorin3A expression, thereby impairing recruitment of Neuropilin-1-expressing monocytes (NEM), TGF-β1 production and endothelial SMAD2/3 activation. TGF-β1 further initiated a feedback loop stimulating endothelial Semaphorin3A expression, thereby amplifying the stabilizing signals. Blocking experiments showed that NEM recruitment required endogenous Semaphorin3A and that TGF-β1 was necessary to start the Semaphorin3A/NEM axis. Conversely, Semaphorin3A treatment promoted NEM recruitment and vessel stabilization despite high VEGF doses or transient adenovir...Continue Reading

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Citations

Jun 15, 2016·Biological Reviews of the Cambridge Philosophical Society·Judy E AndersonRyuichi Tatsumi
Sep 14, 2016·Vascular Pharmacology·Agnieszka JazwaJozef Dulak
Oct 21, 2016·Pharmacology & Therapeutics·A CaporaliG Spinetti
Feb 27, 2018·Journal of Cellular and Molecular Medicine·Ludovic MellyAndrea Banfi
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Aug 29, 2017·Mediators of Inflammation·Jessica ZahnMarietta Herrmann
Apr 13, 2018·EMBO Reports·Elena GroppaAndrea Banfi
Jan 11, 2020·Stem Cells Translational Medicine·Roberto Gianni-BarreraAndrea Banfi
Jun 21, 2019·Journal of Gastrointestinal Cancer·Tuba KarpuzMehmet Artac
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Methods Mentioned

BETA
flow cytometry
FACS
ELISA
PCR

Software Mentioned

Cell Sense
Zen2
GraphPad
GraphPad Prism
ImageJ
Fiji

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