Angiopoietin-like 4 binds neuropilins and cooperates with VEGF to induce diabetic macular edema

Sodhi, Akrit; Ma, Tao; Menon, Deepak; Deshpande, Monika; Jee, Kathleen; Dinabandhu, Aumreetam; Vancel, Jordan; Lu, Da Yong; Montaner, Silvia

doi:10.1172/jci120879

Cited by 63 publications

(57 citation statements)

References 97 publications

(122 reference statements)

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“…MMPs are a family of zinc‐ and calcium‐dependent endopeptidases that can degrade almost all extracellular matrix components 42,43 . VEGF‐A is a dimeric heparin‐binding glycoprotein with pro‐edematous and angiogenic properties 44,45 . Consistent with previous studies, 30,31,33 we found the expression of several MMPs and VEGF‐A was increased, whereas the expression of TIMPs was decreased, in nasal polyps in comparison with control tissues.…”

Section: Discussionsupporting

confidence: 91%

Cold‐inducible RNA‐binding protein contributes to tissue remodeling in chronic rhinosinusitis with nasal polyps

Shi

Deng

et al. 2020

Allergy

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Background Cold‐inducible RNA‐binding protein (CIRP) is a newly identified damage‐associated molecular pattern molecule. Its roles beyond promoting inflammation and in human diseases are poorly understood. This study aimed to investigate the involvement of CIRP in chronic rhinosinusitis with nasal polyps (CRSwNP). Methods Immunohistochemistry, quantitative RT‐PCR, and ELISA were used to detect the expression of CIRP and matrix metalloproteinases (MMPs) in sinonasal mucosal samples and nasal secretions. Human nasal epithelial cells (HNECs) and THP‐1 cells, a human monocytic/macrophage cell line, were cultured to explore the regulation of CIRP expression and MMP expression. Results Cytoplasmic CIRP expression in nasal epithelial cells and CD68+ macrophages in sinonasal tissues, and CIRP levels in nasal secretions were significantly increased in both patients with eosinophilic and noneosinophilic CRSwNP as compared to those in control subjects. IL‐4, IL‐13, IL‐10, IL‐17A, TNF‐α, Dermatophagoides pteronyssinus group 1, and lipopolysaccharide induced the production and secretion of CIRP from HNECs and macrophages differentiated from THP‐1 cells. CIRP promoted MMP2, MMP7, MMP9, MMP12, and vascular endothelial growth factor A (VEGF‐A) production from HNECs, macrophages differentiated from THP‐1 cells, and polyp tissues, which was inhibited by the blocking antibody for Toll‐like receptor 4, but not advanced glycation end products. The expression of MMPs and VEGF‐A in tissues correlated with CIRP levels in nasal secretions in patients with CRSwNP. Conclusions The upregulated production and release of CIRP from nasal epithelial cells and macrophages may contribute to the edema formation in both eosinophilic and noneosinophilic CRSwNP by inducing MMP and VEGF‐A production from epithelial cells and macrophages.

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Section: Discussionsupporting

confidence: 91%

Cold‐inducible RNA‐binding protein contributes to tissue remodeling in chronic rhinosinusitis with nasal polyps

Shi

Deng

et al. 2020

Allergy

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“…NRP1 acts primarily as a co-receptor, binding secreted ligands and forming complexes with the ligand-specific receptors that promote downstream signaling, e.g., vascular endothelial growth factor receptors (VEGFRs) for VEGFA and plexins for class 3 semaphorins. Despite the highly conserved amino acid sequence of the NRP1 cytoplasmic tail across species, which suggests an essential role for this domain ( Figure 1 ), NRP1 lacks an intracellular catalytic activity and is generally considered not to possess intrinsic signaling capabilities [ 46 ], although a few reports seem to indicate that its cytoplasmic tail can signal independently of other receptors [ 47 , 48 ]. Instead, the short intracellular domain of NRP1 acts by recruiting proteins to the cytoplasmic side of NRP1-containing receptor complexes.…”

Section: Nrp1: Molecular Function and Ligandsmentioning

confidence: 99%

Neuropilin 1 Regulation of Vascular Permeability Signaling

Domingues

Fantin

2021

Biomolecules

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The vascular endothelium acts as a selective barrier to regulate macromolecule exchange between the blood and tissues. However, the integrity of the endothelium barrier is compromised in an array of pathological settings, including ischemic disease and cancer, which are the leading causes of death worldwide. The resulting vascular hyperpermeability to plasma molecules as well as leukocytes then leads to tissue damaging edema formation and inflammation. The vascular endothelial growth factor A (VEGFA) is a potent permeability factor, and therefore a desirable target for impeding vascular hyperpermeability. However, VEGFA also promotes angiogenesis, the growth of new blood vessels, which is required for reperfusion of ischemic tissues. Moreover, edema increases interstitial pressure in poorly perfused tumors, thereby affecting the delivery of therapeutics, which could be counteracted by stimulating the growth of new functional blood vessels. Thus, targets must be identified to accurately modulate the barrier function of blood vessels without affecting angiogenesis, as well as to develop more effective pro- or anti-angiogenic therapies. Recent studies have shown that the VEGFA co-receptor neuropilin 1 (NRP1) could be playing a fundamental role in steering VEGFA-induced responses of vascular endothelial cells towards angiogenesis or vascular permeability. Moreover, NRP1 is involved in mediating permeability signals induced by ligands other than VEGFA. This review therefore focuses on current knowledge on the role of NRP1 in the regulation of vascular permeability signaling in the endothelium to provide an up-to-date landscape of the current knowledge in this field.

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“…Finally, NRP2 also binds to Angiopoietin-like 4 (ANGPTL4), a multifunctional protein involved in wound healing and modulation of vascular permeability. The resulting activation of the complex leads to the activation of the RhoA/ROCK signalling pathway, the dissociation of EC-EC junctions, and subsequent retinal vascular leakage [ 99 ] ( Figure 3 e).…”

Section: Endothelial Cell Dysfunctionmentioning

confidence: 99%

“…The NRP2/SEMA3/Plexin complexes are implicated in downregulating angiogenesis and lymphangiogenesis, while promoting vascular permeability [ 91 , 92 , 93 , 94 , 95 , 96 , 97 ]. ( e ) NRP2 binding to ANGPTL4 drives the activation of the RhoA/ROCK signalling pathway to facilitate breakdown of EC-EC junctions and thus increase permeability [ 99 ].…”

Section: Figurementioning

confidence: 99%

Emerging Roles for Neuropilin-2 in Cardiovascular Disease

Harman

Sayers

Chapman

et al. 2020

IJMS

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Cardiovascular disease, the leading cause of death worldwide, is predominantly associated with atherosclerosis. Atherosclerosis is a chronic inflammatory disease characterised by the narrowing of large to medium-sized arteries due to a build-up of plaque. Atherosclerotic plaque is comprised of lipids, extracellular matrix, and several cell types, including endothelial, immune, and vascular smooth muscle cells. Such narrowing of the blood vessels can itself restrict blood flow to vital organs but most severe clinical complications, including heart attacks and strokes, occur when lesions rupture, triggering the blood to clot and obstructing blood flow further down the vascular tree. To circumvent such obstructions, percutaneous coronary intervention or bypass grafts are often required; however, re-occlusion of the treated artery frequently occurs. Neuropilins (NRPs), a multifunctional family of cell surface co-receptors, are expressed by endothelial, immune, and vascular smooth muscle cells and are regulators of numerous signalling pathways within the vasculature. Here, we review recent studies implicating NRP2 in the development of occlusive vascular diseases and discuss how NRP2 could be targeted for therapeutic intervention.

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Angiopoietin-like 4 binds neuropilins and cooperates with VEGF to induce diabetic macular edema

Cited by 63 publications

References 97 publications

Cold‐inducible RNA‐binding protein contributes to tissue remodeling in chronic rhinosinusitis with nasal polyps

Cold‐inducible RNA‐binding protein contributes to tissue remodeling in chronic rhinosinusitis with nasal polyps

Neuropilin 1 Regulation of Vascular Permeability Signaling

Emerging Roles for Neuropilin-2 in Cardiovascular Disease

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