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

Smith, Ross O. (author): Uppsala universitet,Science for Life Laboratory, SciLifeLab,Institutionen för immunologi, genetik och patologi,Uppsala Univ, Rudbeck Lab, Uppsala, Sweden.

Ninchoji, Takeshi (author): Uppsala universitet,Institutionen för immunologi, genetik och patologi,Science for Life Laboratory, SciLifeLab,Uppsala Univ, Rudbeck Lab, Uppsala, Sweden.

Gordon, Emma (author): Uppsala universitet,Science for Life Laboratory, SciLifeLab,Institutionen för immunologi, genetik och patologi,Uppsala Univ, Rudbeck Lab, Uppsala, Sweden.

Dejana, Elisabetta (author): Uppsala universitet,Institutionen för immunologi, genetik och patologi,Science for Life Laboratory, SciLifeLab,Uppsala Univ, Rudbeck Lab, Uppsala, Sweden.;IFOM IEO, Campus Via Adamello, Milan, Italy.

Claesson-Welsh, Lena (author): Uppsala universitet,Science for Life Laboratory, SciLifeLab,Institutionen för immunologi, genetik och patologi,Uppsala Univ, Rudbeck Lab, Uppsala, Sweden.

(creator_code:org_t)

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Abstract Subject headings

Edema stemming from leaky blood vessels is common in eye diseases such as agerelated 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.

By the author/editor: Smith, Ross O.; Ninchoji, Takesh ...; Gordon, Emma; Andre, Helder; Dejana, Elisabet ...; Vestweber, Dietm ...; show more...; Kvanta, Anders; Claesson-Welsh, ...; show less...

About the subject

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Cell and Molecul ...

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