Journal Article

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

Lacoste, Baptiste, Tata, Aleksandra, Kopycinska, Justyna, Wang, Jia-Huai, Hagan, Nellwyn, Oh, Won-Jong, Gu, Chenghua, Gelfand, Maria V, Bischoff, Joyce, Kang, Kyu-Tae

2014

Overview

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. Blood flows through blood vessels to carry oxygen and nutrients towards, and waste away from, the cells of the body. New blood vessels are formed not only during development but also throughout life as part of normal tissue growth and repair. However, blood vessels may also form as a consequence of diseases, such as cancer. For example, tumors often stimulate the growth of new blood vessels to ensure a good supply of blood carrying nutrients and oxygen. As such, some anti-cancer therapies try to stop blood vessels from developing in an attempt to slow down or prevent tumor growth. New blood vessels often form by branching off from existing vessels. One molecule that stimulates this branching process is called vascular endothelial growth factor (or VEGF for short). Three ‘receptor’ proteins found on the outside of cells can bind to the VEGF molecule and then trigger a response inside the cell that guides the development of new blood vessels. VEGF and its receptor proteins—including one called NRP1—are being investigated as a possible target for drugs that could treat cancer and other diseases affecting blood vessels. However, the exact mechanisms that control the formation of new blood vessels are not fully understood, which makes it difficult to develop these treatments. Now Gelfand et al. have created mice whose NRP1 receptors cannot bind VEGF. These mice unexpectedly survive to adulthood and develop normal blood vessels. This outcome is in contrast to mice that lack NRP1, which normally die as embryos and have severe defects with their nerves and blood vessels. Gelfand et al. instead found that mice that only lack NRP1 in the cells of their blood vessels had less of another receptor protein called VEGFR2 on the surface of these cells. This result suggests that NRP1 controls blood vessel development, not by binding to VEGF but by affecting how much of the VEGFR2 receptor is available to interact with VEGF. These findings challenge the long-held view of how NRP1 functions and lead Gelfand et al. to suggest a new mechanism: NRP1 interacts with VEGFR2, rather than with VEGF, to control the formation of new blood vessels. Future work will aim to uncover how these interactions regulate the normal development of blood vessels, and if other molecules that bind to NRP1 are involved in this process. Furthermore, these findings may help to guide the on-going efforts to develop drugs that target NRP1 into treatments that are effective against diseases that involve problems with blood vessels—including diabetes, immune disorders, and cancer.

• Publisher: eLife Sciences Publications Ltd,eLife Sciences Publications, Ltd
• Subject: Amino Acid Sequence / Angiogenesis / Animals / Animals, Newborn / Binding Sites / Cancer / Cell Membrane - metabolism / Cercopithecus aethiops / COS Cells / Defects / developmental angiogenesis / Developmental Biology and Stem Cells / HEK293 Cells / Humans / Hypotheses / Kinases / Ligands / Medical schools / Mice / Microscopy / Molecular Sequence Data / Morphogenesis / mouse genetic / Mutation / Mutation - genetics / Neovascularization, Physiologic / Neuropilin / Neuropilin-1 / Neuropilin-1 - chemistry / Neuropilin-1 - metabolism / Neurosciences / Phosphatase / Point mutation / Protein Binding / Rats / Surgery / Vascular diseases / Vascular endothelial growth factor / Vascular Endothelial Growth Factor Receptor-2 - metabolism / VEGF / VEGFR2 / Veins & arteries