Neuropilin-1 functions as a VEGFR2 co-receptor to guide developmental angiogenesis independent of ligand binding
- Harvard Medical School, United States
- Boston Children's Hospital, Harvard Medical School, United States
- 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.
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Author details
Reviewing Editor
- Jeremy Nathans, Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, United States
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).
Version history
- Received: June 18, 2014
- Accepted: September 20, 2014
- Accepted Manuscript published: September 22, 2014 (version 1)
- Version of Record published: October 15, 2014 (version 2)
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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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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