期刊
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
卷 41, 期 4, 页码 1374-1389出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/ATVBAHA.121.315941
关键词
cadherins; diabetic retinopathy; permeability; syndecans; vascular endothelial growth factor A
资金
- Arthritis Research UK [19207, 21177]
- Fight for Sight [1558/59]
- Barts and The London Charity [MGU0313]
- Queen Mary Innovations
- William Harvey Research Foundation
- Macular Society
- Dunhill Medical Trust [RPGF1906\173]
- Academy of Finland
- Paivikki and Sakari Sohlberg Foundation
- Instrumentarium Research Foundation
- Diabetes Wellness Foundation (DWF)
- Pirkanmaa Hospital District Research Foundation
- Tampere Tuberculosis Foundation
- Finnish Cultural Foundation
- MRC [MR/K003003/1] Funding Source: UKRI
This study establishes the crucial role of SDC4 in pathological angiogenesis, particularly in eye diseases and tumor development. SDC4 is identified as a downstream mediator of VEGFA-induced vascular endothelial cadherin internalization, representing a potential target for antiangiogenic therapies.
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.
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