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Pathological Angiogenesis Requires Syndecan-4 for Efficient VEGFA-Induced VE-Cadherin Internalization.

De Rossi, G; Vähätupa, M; Cristante, E; Arokiasamy, S; Liyanage, SE; May, U; Pellinen, L; ... Whiteford, JR; + view all (2021) Pathological Angiogenesis Requires Syndecan-4 for Efficient VEGFA-Induced VE-Cadherin Internalization. Arteriosclerosis, Thrombosis and Vascular Biology , 41 (4) pp. 1374-1389. 10.1161/ATVBAHA.121.315941. Green open access

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Abstract

Objective: VEGFA (Vascular endothelial growth factor A) and its receptor VEGFR2 (vascular endothelial growth factor receptor 2) drive angiogenesis in several pathologies, including diabetic retinopathy, wet age-related macular degeneration, and cancer. Studies suggest roles for HSPGs (heparan sulfate proteoglycans) in this process, although the nature of this involvement remains elusive. Here, we set to establish the role of the HSPG SDC4 (syndecan-4) in pathological angiogenesis. / Approach and Results: We report that angiogenesis is impaired in mice null for SDC4 in models of neovascular eye disease and tumor development. Our work demonstrates that SDC4 is the only SDC whose gene expression is upregulated during pathological angiogenesis and is selectively enriched on immature vessels in retinas from diabetic retinopathy patients. Combining in vivo and tissue culture models, we identified SDC4 as a downstream mediator of functional angiogenic responses to VEGFA. We found that SDC4 resides at endothelial cell junctions, interacts with vascular endothelial cadherin, and is required for its internalization in response to VEGFA. Finally, we show that pathological angiogenic responses are inhibited in a model of wet age-related macular degeneration by targeting SDC4. / Conclusions: We show that SDC4 is a downstream mediator of VEGFA-induced vascular endothelial cadherin internalization during pathological angiogenesis and a potential target for antiangiogenic therapies.

Type: Article
Title: Pathological Angiogenesis Requires Syndecan-4 for Efficient VEGFA-Induced VE-Cadherin Internalization.
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1161/ATVBAHA.121.315941
Publisher version: https://doi.org/10.1161/ATVBAHA.121.315941
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: diabetic retinopathy; cadherins; syndecans; permeability; vascular endothelial growth factor A
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology
URI: https://discovery.ucl.ac.uk/id/eprint/10125683
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