Neuropilin-1 Binds to VEGF121 and Regulates Endothelial Cell Migration and Sprouting

Pan, Qi; Chathery, Yvan; Wu, Yan; Rathore, Nisha; Tong, Raymond K.; Peale, Franklin; Bagri, Anil; Tessier‐Lavigne, Marc; Koch, Alexander W.; Watts, Ryan J.

doi:10.1074/jbc.m703554200

Cited by 187 publications

(181 citation statements)

References 31 publications

Supporting

Mentioning

168

Contrasting

Unclassified

Order By: Relevance

“…Figures 4 and 6 of that paper show that VEGF-A121a produced by a number of different sources binds to NRP1. 27 This shows that well-characterized VEGF-A121a, possessing the correct sequence (including exon 8a), has a three dimensional structure that enables its binding to NRP1 with binding affinity comparable to VEGF-A165a (K d of 220 nM compared to K d of 110 nM). Note that SPR measurements represent the affinities for the interaction of a ligand with monomeric truncated NRP1, comprising only the a1/12-b1/b2 domains and lacking the MAM domain known to induce NRP oligomerization, 28 the transmembrane domain known to homodimerize 29 and the NRP1 GAG modification 30 , which may explain why these SPR-measured affinities are lower than those measured for on-cell VEGF-NRP interactions.…”

Section: Evidence Supporting Direct Vegf-a121a Binding To Neuropilinsmentioning

confidence: 87%

“…HS chains on endothelial HSPGs stabilize this complex by binding to NRP1, VEGFR2 domain 6–7 and VEGF-A165a. (F) Binding (at lower affinity 18 , 27 ) of VEGF-A121a to NRP1 and VEGFR2 may form a weak extracellular bridge that can not be captured by immunoprecipitaion and cross-linking or (G) VEGF-A121a may alternatively only bind to VEGFR2 and activate the receptor dimer, (H) VEGF-A121a may predominantly bind to abundant NRP1 species on endothelial cell surface to activate the VEGFR2 receptor dimer. Upon binding to the receptors, VEGF-A121a and VEGF-A165a each may induce a conformationally distinct VEGFR/NRP/VEGF signaling complex (comparing E with F, G and H).…”

Section: Evidence That the Exon 8a Domain Which Vegf-a121a Has Is Rmentioning

confidence: 99%

“…Upon binding to the receptors, VEGF-A121a and VEGF-A165a each may induce a conformationally distinct VEGFR/NRP/VEGF signaling complex (comparing E with F, G and H). The different conformations permit different signaling, but NRP can modulate both 15 , 27 . Alternatively, VEGF-A121a and VEGF-A165a each may induce a VEGFR/NRP/VEGF signaling complex with similar conformation, but with different stability.…”

Section: Evidence That the Exon 8a Domain Which Vegf-a121a Has Is Rmentioning

confidence: 99%

“…27 VEGF-A109 is a proteolytically-processed VEGF-A isoform which only contains exons 1–4 and most of exon 5; since it lacks the exon 8a-encoded sequence it should not and does not bind to Neuropilins. Figures 4 and 6 of that paper show that VEGF-A121a produced by a number of different sources binds to NRP1.…”

Section: Evidence Supporting Direct Vegf-a121a Binding To Neuropilinsmentioning

confidence: 99%

“…2D and 4C of. 27 , 32 Other technical considerations for any experiment probing ligand-receptor interactions in general include: 1) the presence of tags (e.g. myc, Flag) on purified or purchased VEGF-A121a that may sterically interfere with ligand-receptor binding; and 2) expression and purification in E. coli instead of mammalian cells, which may cause incorrect posttranslational modifications or VEGF-A disulfide bond formation, or low affinity of VEGF-A121a due to improper folding/structure.…”

Section: Evidence Supporting Direct Vegf-a121a Binding To Neuropilinsmentioning

confidence: 99%

See 4 more Smart Citations

VEGF-A121a binding to Neuropilins – A concept revisited

Sarabipour

Gabhann

2017

Cell Adhesion & Migration

View full text Add to dashboard Cite

All known splice isoforms of vascular endothelial growth factor A (VEGF-A) can bind to the receptor tyrosine kinases VEGFR-1 and VEGFR-2. We focus here on VEGF-A121a and VEGF-A165a, two of the most abundant VEGF-A splice isoforms in human tissue1, and their ability to bind the Neuropilin co-receptors NRP1 and NRP2. The Neuropilins are key vascular, immune, and nervous system receptors on endothelial cells, neuronal axons, and regulatory T cells respectively. They serve as co-receptors for the Plexins in Semaphorin binding on neuronal and vascular endothelial cells, and for the VEGFRs in VEGF binding on vascular and lymphatic endothelial cells, and thus regulate the initiation and coordination of cell signaling by Semaphorins and VEGFs.2 There is conflicting evidence in the literature as to whether only heparin-binding VEGF-A isoforms – that is, isoforms with domains encoded by exons 6 and/or 7 plus 8a – bind to Neuropilins on endothelial cells. While it is clear that VEGF-A165a binds to both NRP1 and NRP2, published studies do not all agree on the ability of VEGF-A121a to bind NRPs. Here, we review and attempt to reconcile evidence for and against VEGF-A121a binding to Neuropilins. This evidence suggests that, in vitro, VEGF-A121a can bind to both NRP1 and NRP2 via domains encoded by exons 5 and 8a; in the case of NRP1, VEGF-A121a binds with lower affinity than VEGF-A165a. In in vitro cell culture experiments, both NRP1 and NRP2 can enhance VEGF-A121a-induced phosphorylation of VEGFR2 and downstream signaling including proliferation. However, unlike VEGFA-165a, experiments have shown that VEGF-A121a does not ‘bridge’ VEGFR2 and NRP1, i.e. it does not bind both receptors simultaneously at their extracellular domain. Thus, the mechanism by which Neuropilins potentiate VEGF-A121a-mediated VEGFR2 signaling may be different from that for VEGF-A165a. We suggest such an alternate mechanism: interactions between NRP1 and VEGFR2 transmembrane (TM) and intracellular (IC) domains.

show abstract

Section: Evidence Supporting Direct Vegf-a121a Binding To Neuropilinsmentioning

confidence: 87%

Section: Evidence That the Exon 8a Domain Which Vegf-a121a Has Is Rmentioning

confidence: 99%

Section: Evidence That the Exon 8a Domain Which Vegf-a121a Has Is Rmentioning

confidence: 99%

Section: Evidence Supporting Direct Vegf-a121a Binding To Neuropilinsmentioning

confidence: 99%

Section: Evidence Supporting Direct Vegf-a121a Binding To Neuropilinsmentioning

confidence: 99%

See 3 more Smart Citations

VEGF-A121a binding to Neuropilins – A concept revisited

Sarabipour

Gabhann

2017

Cell Adhesion & Migration

View full text Add to dashboard Cite

show abstract

Molecular and Cellular Mechanisms of Vascular Development

Bolton¹,

Naylor²,

Ruhrberg³

2019

Encyclopedia of Life Sciences

View full text Add to dashboard Cite

Blood vessels form an extensive organ system that enables gas exchange, delivers nutrients and removes waste products from tissues and is, therefore, essential for vertebrate life. Blood vessels additionally regulate leukocyte trafficking to support immune system function and transport endocrine hormones for the systemic regulation of physiological processes. During embryonic development, blood vessels also secrete cues that regulate the formation of other organs. To ensure that functional vasculature forms in the embryo, a large number of molecules regulate a wide range of cellular mechanisms that collectively act on the endothelial cells that form the inner lining of all blood vessels. These molecular and cellular mechanisms may be reactivated after birth to induce blood vessel growth that is beneficial by countering tissue ischemia or pathological if excessive or dysfunctional. Understanding developmental blood vessel growth, therefore, provides knowledge that may be used to develop new therapeutic strategies for a range of diseases. Key Concepts The circulatory system is the first organ to form during vertebrate embryogenesis and is required for the subsequent development of other organs. The circulatory system is the first organ to form during vertebrate embryogenesis. Proper blood vessel growth and remodeling is required for the subsequent development of other organs. Blood vessel development can be studied using the embryonic mouse hindbrain and perinatal mouse retina. Many molecular pathways synergise to regulate blood vessel growth. Elucidating the mechanisms of vascular development may advance novel therapies to treat vascular insufficiency in ischemic diseases.

show abstract

Biomaterial Based Strategies for Engineering New Lymphatic Vasculature

Campbell

Silva

2020

Adv Healthcare Materials

View full text Add to dashboard Cite

The lymphatic system is essential for tissue regeneration and repair due to its pivotal role in resolving inflammation, immune cell surveillance, lipid transport, and maintaining tissue homeostasis. Loss of functional lymphatic vasculature is directly implicated in a variety of diseases, including lymphedema, obesity, and the progression of cardiovascular diseases. Strategies that stimulate the formation of new lymphatic vessels (lymphangiogenesis) could provide an appealing new approach to reverse the progression of these diseases. However, lymphangiogenesis is relatively understudied and stimulating therapeutic lymphangiogenesis faces challenges in precise control of lymphatic vessel formation. Biomaterial delivery systems could be used to unleash the therapeutic potential of lymphangiogenesis for a variety of tissue regenerative applications due to their ability to achieve precise spatial and temporal control of multiple therapeutics, direct tissue regeneration, and improve the survival of delivered cells. In this review, the authors begin by introducing therapeutic lymphangiogenesis as a target for tissue regeneration, then an overview of lymphatic vasculature will be presented followed by a description of the mechanisms responsible for promoting new lymphatic vessels. Importantly, this work will review and discuss current biomaterial applications for stimulating lymphangiogenesis. Finally, challenges and future directions for utilizing biomaterials for lymphangiogenic based treatments are considered.

show abstract

Neuropilin-1 Binds to VEGF121 and Regulates Endothelial Cell Migration and Sprouting

Cited by 187 publications

References 31 publications

VEGF-A121a binding to Neuropilins – A concept revisited

VEGF-A121a binding to Neuropilins – A concept revisited

Molecular and Cellular Mechanisms of Vascular Development

Biomaterial Based Strategies for Engineering New Lymphatic Vasculature

Contact Info

Product

Resources

About