Neuropilin-1 functions as a VEGFR2 co-receptor to guide developmental angiogenesis independent of ligand binding
Maria V Gelfand,
Nellwyn Hagan,
Aleksandra Tata,
Won-Jong Oh,
Baptiste Lacoste,
Kyu-Tae Kang,
Justyna Kopycinska,
Joyce Bischoff,
Jia-Huai Wang,
Chenghua Gu
Affiliations
Maria V Gelfand
Department of Neurobiology, Harvard Medical School, Boston, United States
Nellwyn Hagan
Department of Neurobiology, Harvard Medical School, Boston, United States
Aleksandra Tata
Department of Neurobiology, Harvard Medical School, Boston, United States
Won-Jong Oh
Department of Neurobiology, Harvard Medical School, Boston, United States; Korea Brain Research Institute, Daegu, Republic of Korea
Baptiste Lacoste
Department of Neurobiology, Harvard Medical School, Boston, United States
Kyu-Tae Kang
Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, United States; Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, United States; College of Pharmacy, Duksung Women's University, Seoul, Republic of Korea
Justyna Kopycinska
Department of Neurobiology, Harvard Medical School, Boston, United States
Joyce Bischoff
Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, United States; Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, United States
Jia-Huai Wang
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States; Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States
Chenghua Gu
Department of Neurobiology, Harvard Medical School, Boston, United States
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. In this study, 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.
