Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 122, Issue 12, Pages 4424-4438Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI64537
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Funding
- NIH [R01HL-093242, P20 RR018758, NS36251, DK45735, P01HL085607, R01 HL085789, R01 HL109420]
- Oklahoma Center for Advanced Science and Technology (OCAST)
- American Heart Association [0835544N]
- Associazione Italiana per la Ricerca sul Cancro (AIRC)
- Association for International Cancer Research - UK (AICR-UK)
- Telethon
- CARIPLO
- Interlink
- COFIN/PRIN
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Epsins are a family of ubiquitin-binding, endocytic clathrin adaptors. Mice lacking both epsins 1 and 2 (Epn1/2) die at embryonic day 10 and exhibit an abnormal vascular phenotype. To examine the angiogenic role of endothelial epsins, we generated mice with constitutive or inducible deletion of Epn1/2 in vascular endothelium. These mice exhibited no abnormal phenotypes under normal conditions, suggesting that lack of endothelial epsins 1 and 2 did not affect normal blood vessels. In tumors, however, loss of epsins 1 and 2 resulted in disorganized vasculature, significantly increased vascular permeability, and markedly retarded tumor growth. Mechanistically, we show that VEGF promoted binding of epsin to ubiquitinated VEGFR2. Loss of epsins 1 and 2 specifically impaired endocytosis and degradation of VEGFR2, which resulted in excessive VEGF signaling that compromised tumor vascular function by exacerbating nonproductive leaky angiogenesis. This suggests that tumor vasculature requires a balance in VEGF signaling to provide sufficient productive angiogenesis for tumor development and that endothelial epsins 1 and 2 negatively regulate the output of VEGF signaling. Promotion of excessive VEGF signaling within tumors via a block of epsin 1 and 2 function may represent a strategy to prevent normal angiogenesis in cancer patients who are resistant to anti-VEGF therapies.
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