Neuropilin-1 functions as a VEGFR2 co-receptor to guide developmental angiogenesis independent of ligand binding

  1. Maria V Gelfand
  2. Nellwyn Hagan
  3. Aleksandra Tata
  4. Won-Jong Oh
  5. Baptiste Lacoste
  6. Kyu-Tae Kang
  7. Justyna Kopycinska
  8. Joyce Bischoff
  9. Jia-Huai Wang
  10. Chenghua Gu  Is a corresponding author
  1. Harvard Medical School, United States
  2. Boston Children's Hospital, Harvard Medical School, United States
  3. Dana-Farber Cancer Institute, Harvard Medical School, United States

Abstract

During development, tissue repair, and tumor growth, most blood vessel networks are generated through angiogenesis. Vascular endothelial growth factor (VEGF) is a key regulator of this process and currently, both VEGF and its receptors, VEGFR1, VEGFR2, and Neuropilin1 (NRP1), are targeted in therapeutic strategies for vascular disease and cancer. NRP1 is essential for vascular morphogenesis, but how NRP1 functions to guide vascular development has not been completely elucidated. Here, we generated a mouse line harboring a point mutation in the endogenous Nrp1 locus that selectively abolishes VEGF-NRP1 binding (Nrp1VEGF-). Nrp1VEGF- mutants survive to adulthood with normal vasculature revealing that NRP1 functions independent of VEGF-NRP1 binding during developmental angiogenesis. Moreover, we found that Nrp1-deficient vessels have reduced VEGFR2 surface expression in vivo demonstrating that NRP1 regulates its co-receptor, VEGFR2. Given the resources invested in NRP1 targeted anti-angiogenesis therapies, our results will be integral for developing strategies to re-build vasculature in disease.

Article and author information

Author details

  1. Maria V Gelfand

    Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Nellwyn Hagan

    Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Aleksandra Tata

    Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Won-Jong Oh

    Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Baptiste Lacoste

    Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Kyu-Tae Kang

    Boston Children's Hospital, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Justyna Kopycinska

    Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Joyce Bischoff

    Boston Children's Hospital, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Jia-Huai Wang

    Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Chenghua Gu

    Harvard Medical School, Boston, United States
    For correspondence
    Chenghua_Gu@hms.harvard.edu
    Competing interests
    The authors declare that no competing interests exist.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All animals were handled according to approved institutional animal care and use committee (IACUC) protocols at Harvard Medical School (IACUC Study ID: IS00000045).

Copyright

© 2014, Gelfand et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Maria V Gelfand
  2. Nellwyn Hagan
  3. Aleksandra Tata
  4. Won-Jong Oh
  5. Baptiste Lacoste
  6. Kyu-Tae Kang
  7. Justyna Kopycinska
  8. Joyce Bischoff
  9. Jia-Huai Wang
  10. Chenghua Gu
(2014)
Neuropilin-1 functions as a VEGFR2 co-receptor to guide developmental angiogenesis independent of ligand binding
eLife 3:e03720.
https://doi.org/10.7554/eLife.03720

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https://doi.org/10.7554/eLife.03720