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KIF13B mediates VEGFR2 recycling to modulate vascular permeability

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Abstract

Excessive vascular endothelial growth factor-A (VEGF-A) signaling induces vascular leakage and angiogenesis in diseases. VEGFR2 trafficking to the cell surface, mediated by kinesin-3 family protein KIF13B, is essential to respond to VEGF-A when inducing angiogenesis. However, the precise mechanism of how KIF13B regulates VEGF-induced signaling and its effects on endothelial permeability is largely unknown. Here we show that KIF13B-mediated recycling of internalized VEGFR2 through Rab11-positive recycling vesicle regulates endothelial permeability. Phosphorylated VEGFR2 at the cell–cell junction was internalized and associated with KIF13B in Rab5-positive early endosomes. KIF13B mediated VEGFR2 recycling through Rab11-positive recycling vesicle. Inhibition of the function of KIF13B attenuated phosphorylation of VEGFR2 at Y951, SRC at Y416, and VE-cadherin at Y685, which are necessary for endothelial permeability. Failure of VEGFR2 trafficking to the cell surface induced accumulation and degradation of VEGFR2 in lysosomes. Furthermore, in the animal model of the blinding eye disease wet age-related macular degeneration (AMD), inhibition of KIF13B-mediated VEGFR2 trafficking also mitigated vascular leakage. Thus, the present results identify the fundamental role of VEGFR2 recycling to the cell surface in mediating vascular permeability, which suggests a promising strategy for mitigating vascular leakage associated with inflammatory diseases.

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Data and materials availability

The authors declare that the data supporting the findings of this study are available within the paper and its Supplementary materials. Further information and requests for resources and reagents should be directed to and will be fulfilled by the Lead Contact, Kaori Yamada (horiguch@uic.edu).

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Acknowledgements

We thank Dr. Toshihiko Hanada (Tufts University, Boston, MA, USA) for sharing a monoclonal antibody against KIF13B [1]. Portions of this work were carried out in the Fluorescent Imaging Core via the Research Resources Center (RRC) at the University of Illinois at Chicago (UIC). Schematic figures are created with BioRender.com.

Funding

This work was supported by NIH R01EY029339 (KHY), Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2021R1A6A3A03044037) to HDC, and a core grant NIH P30EY001792 to the Department of Ophthalmology.

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Conceptualization: H-DC, KHY. Methodology: H-DC, NTTN, KHY. Investigation: H-DC, NTTN, CZ, KT, NAS, TN. Visualization: H-DC, NTTN, CZ, KT, NAS. Funding acquisition: H-DC, TN, KHY. Project administration: KHY. Supervision: KHY. Writing—original draft: H-DC, KHY. Writing—review and editing: NTTN, KHY. Data and materials availability: The authors declare that the data supporting the findings of this study are available within the paper and its Supplementary materials. Further information and requests for resources and reagents should be directed to and will be fulfilled by the Lead Contact, Kaori Yamada (horiguch@uic.edu).

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Correspondence to Kaori H. Yamada.

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All animal experiments were carried out in compliance with the relevant laws, and institutional guidelines and were approved by the Animal Care Committees administered through the Office of Animal Care and Institutional Biosafety at the University of Illinois at Chicago.

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Cho, HD., Nhàn, N.T.T., Zhou, C. et al. KIF13B mediates VEGFR2 recycling to modulate vascular permeability. Cell. Mol. Life Sci. 80, 91 (2023). https://doi.org/10.1007/s00018-023-04752-5

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