Neuropilin 1 Involvement in Choroidal and Retinal Neovascularisation

Fernández-Robredo, Patricia; Selvam, Senthil; Powner, Michael B.; Sim, Dawn A; Fruttiger, Marcus

doi:10.1371/journal.pone.0169865

Cited by 17 publications

(10 citation statements)

References 36 publications

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“…In sum, while a role for endothelial‐resident NRP1 has been demonstrated in choroidal and retinal neovascularization (Fernandez‐Robredo et al, 2017), we provide evidence that NRP1‐expressing immune cells contribute to CNV. Collectively, we provide rationale for therapeutic targeting of NRP1 ligands or NRP1‐expressing myeloid cells for exudative AMD.…”

Section: Discussionsupporting

confidence: 63%

Myeloid‐resident neuropilin‐1 promotes choroidal neovascularization while mitigating inflammation

et al. 2021

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Age‐related macular degeneration (AMD) in its various forms is a leading cause of blindness in industrialized countries. Here, we provide evidence that ligands for neuropilin‐1 (NRP1), such as Semaphorin 3A and VEGF‐A, are elevated in the vitreous of patients with AMD at times of active choroidal neovascularization (CNV). We further demonstrate that NRP1‐expressing myeloid cells promote and maintain CNV. Expression of NRP1 on cells of myeloid lineage is critical for mitigating production of inflammatory factors such as IL6 and IL1β. Therapeutically trapping ligands of NRP1 with an NRP1‐derived trap reduces CNV. Collectively, our findings identify a role for NRP1‐expressing myeloid cells in promoting pathological angiogenesis during CNV and introduce a therapeutic approach to counter neovascular AMD.

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Section: Discussionsupporting

confidence: 63%

Myeloid‐resident neuropilin‐1 promotes choroidal neovascularization while mitigating inflammation

et al. 2021

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“…This conjecture is supported by our finding that, when compared with aflibercept, intravitreal administration of BI-Y into the eye of mice with OIR significantly reduces the size of the avascular area and significantly increases tip cell density at the avascular front. These results align with previous work demonstrating the central role of Sema3A and Nrp-1 in angiogenesis and endothelial leakage using mouse models (Fantin et al, 2014, Fernández-Robredo et al, 2017, Nakamura et al, 2022, Zippel et al, 2022.…”

Section: Bi-y Does Not Affect Vegf-a-dependent Laser-induced Choroidalsupporting

confidence: 92%

“…In the OIR model, mice with Nrp-1 hypomorphism (partial loss of function) show reduced angiogenesis compared with wild-type mice (Fantin et al, 2014). In addition, OIR mice lacking endothelial Nrp-1 have reduced leakage into the retina (Fernández-Robredo et al, 2017). BI-Y, a monoclonal IgG1 type antibody for intravitreal injection that binds to the Adomain of Nrp-1 and antagonizes its biologic effects.…”

mentioning

confidence: 99%

BI-Y, an Neuropilin-1 Antagonist, Enhances Revascularization and Prevents Vascular Endothelial Growth Factor-A Induced Retinal Hyperpermeability in Rodent Models of Retinopathies

Thomas

Low

Hansen

et al. 2023

J Pharmacol Exp Ther

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Diabetic retinopathy (DR) is a leading cause of vision loss in working-age adults. Despite an established standard of care for advanced forms of DR, some patients continue to lose vision following treatment. This may be due to the development of diabetic macular ischemia (DMI), which has no approved treatment. Neuropilin-1 (Nrp-1) is a co-receptor with two ligand-binding domains, with semaphorin-3A (Sema3A) binding to the A domain and vascular endothelial growth factor-A (VEGF-A) binding to the B-domain. Sema3A directs a subset of neuronal growth cones as well as blood vessel growth by repulsion; when bound to Nrp-1, VEGF-A mediates vascular permeability and angiogenesis. Modulating Nrp-1 could therefore address multiple complications arising from DR, such as diabetic macular edema (DME) and DMI. BI-Y is a monoclonal antibody that binds to the Nrp-1 A-domain, antagonizing the effects of the ligand Sema3A and inhibiting VEGF-A-induced vascular permeability. This series of in vitro and in vivo studies examined the binding kinetics of BI-Y to Nrp-1 with and without VEGF-A 165 , the effect of BI-Y on Sema3A-induced cytoskeletal collapse, the effect of BI-Y on VEGF-A 165 -induced angiogenesis, neovascularization, cell integrity loss and permeability, and on retinal revascularization. The data show that BI-Y binds to Nrp-1 and inhibits Sema3A-induced cytoskeletal collapse in vitro, may enhance revascularization of ischemic areas in an oxygen-induced retinopathy mouse model, and prevents VEGF-A-induced retinal hyperpermeability in rats. However, BI-Y does not interfere with VEGF-A-dependent choroidal neovascularization. These results support further investigation of BI-Y as a potential treatment for DMI and DME.

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“…In ECs, NRPs modulate VEGFR signaling, enhancing migration ( Soker et al, 1998 ) and survival ( Favier et al, 2006 ). In addition, NRP1 has also been implicated in the spatial organization of ECs within angiogenic sprouts ( Fantin et al, 2013 ; Kawamura et al, 2008 ) and in mouse models of pathological choroidal and retinal neovascularization ( Dejda et al, 2014 , 2016 ; Fernandez-Robredo et al, 2017 ).…”

Section: Molecular Signaling Mechanisms In the Vegf Familymentioning

confidence: 99%

VEGFR1 signaling in retinal angiogenesis and microinflammation

Uemura

Fruttiger

D’Amore

et al. 2021

Progress in Retinal and Eye Research

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191

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Five vascular endothelial growth factor receptor (VEGFR) ligands (VEGF-A, -B, –C, -D, and placental growth factor [PlGF]) constitute the VEGF family. VEGF-A binds VEGF receptors 1 and 2 (VEGFR1/2), whereas VEGF-B and PlGF only bind VEGFR1. Although much research has been conducted on VEGFR2 to elucidate its key role in retinal diseases, recent efforts have shown the importance and involvement of VEGFR1 and its family of ligands in angiogenesis, vascular permeability, and microinflammatory cascades within the retina. Expression of VEGFR1 depends on the microenvironment, is differentially regulated under hypoxic and inflammatory conditions, and it has been detected in retinal and choroidal endothelial cells, pericytes, retinal and choroidal mononuclear phagocytes (including microglia), Müller cells, photoreceptor cells, and the retinal pigment epithelium. Whilst the VEGF-A decoy function of VEGFR1 is well established, consequences of its direct signaling are less clear. VEGFR1 activation can affect vascular permeability and induce macrophage and microglia production of proinflammatory and proangiogenic mediators. However the ability of the VEGFR1 ligands (VEGF-A, PlGF, and VEGF-B) to compete against each other for receptor binding and to heterodimerize complicates our understanding of the relative contribution of VEGFR1 signaling alone toward the pathologic processes seen in diabetic retinopathy, retinal vascular occlusions, retinopathy of prematurity, and age-related macular degeneration. Clinically, anti-VEGF drugs have proven transformational in these pathologies and their impact on modulation of VEGFR1 signaling is still an opportunity-rich field for further research.

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Neuropilin 1 Involvement in Choroidal and Retinal Neovascularisation

Cited by 17 publications

References 36 publications

Myeloid‐resident neuropilin‐1 promotes choroidal neovascularization while mitigating inflammation

Myeloid‐resident neuropilin‐1 promotes choroidal neovascularization while mitigating inflammation

BI-Y, an Neuropilin-1 Antagonist, Enhances Revascularization and Prevents Vascular Endothelial Growth Factor-A Induced Retinal Hyperpermeability in Rodent Models of Retinopathies

VEGFR1 signaling in retinal angiogenesis and microinflammation

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