Vascular permeability in retinopathy is regulated by VEGFR2 Y949 signaling to VE-cadherin.

Autor:	Smith RO; Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Science for Life Laboratory Uppsala University, Uppsala, Sweden., Ninchoji T; Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Science for Life Laboratory Uppsala University, Uppsala, Sweden., Gordon E; Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Science for Life Laboratory Uppsala University, Uppsala, Sweden., André H; Department of Clinical Neuroscience, Division of Eye and Vision, St. Erik Eye Hospital, Karolinska Institutet, Stockholm, Sweden., Dejana E; Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Science for Life Laboratory Uppsala University, Uppsala, Sweden.; IFOM-IEO Campus Via Adamello, Milan, Italy., Vestweber D; Max Planck Institute for Molecular Biomedicine, Münster, Germany., Kvanta A; Department of Clinical Neuroscience, Division of Eye and Vision, St. Erik Eye Hospital, Karolinska Institutet, Stockholm, Sweden., Claesson-Welsh L; Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Science for Life Laboratory Uppsala University, Uppsala, Sweden.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2020 Apr 21; Vol. 9. Date of Electronic Publication: 2020 Apr 21.
DOI:	10.7554/eLife.54056
Abstrakt:	Edema stemming from leaky blood vessels is common in eye diseases such as age-related macular degeneration and diabetic retinopathy. Whereas therapies targeting vascular endothelial growth factor A (VEGFA) can suppress leakage, side-effects include vascular rarefaction and geographic atrophy. By challenging mouse models representing different steps in VEGFA/VEGF receptor 2 (VEGFR2)-induced vascular permeability, we show that targeting signaling downstream of VEGFR2 pY949 limits vascular permeability in retinopathy induced by high oxygen or by laser-wounding. Although suppressed permeability is accompanied by reduced pathological neoangiogenesis in oxygen-induced retinopathy, similarly sized lesions leak less in mutant mice, separating regulation of permeability from angiogenesis. Strikingly, vascular endothelial (VE)-cadherin phosphorylation at the Y685, but not Y658, residue is reduced when VEGFR2 pY949 signaling is impaired. These findings support a mechanism whereby VE-cadherin Y685 phosphorylation is selectively associated with excessive vascular leakage. Therapeutically, targeting VEGFR2-regulated VE-cadherin phosphorylation could suppress edema while leaving other VEGFR2-dependent functions intact. Competing Interests: RS, TN, EG, HA, ED, DV, AK, LC No competing interests declared (© 2020, Smith et al.)
Databáze:	MEDLINE
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