Ischemia‐induced Netrin‐4 promotes neovascularization through endothelial progenitor cell activation via Unc‐5 Netrin receptor B

Lee, Na Geum; Jeung, In Cheul; Heo, Soon Chul; Song, Jinhoi; Kim, Wooil; Hwang, Byungtae; Kwon, Min‐Gi; Kim, Yeon‐Gu; Lee, Jangwook; Park, Jong‐Gil; Shin, Min‐Gyeong; Cho, Young‐Lai; Son, Mi‐Young; Bae, Kwang‐Hee; Lee, Sang‐Hyun; Kim, Jae Ho; Min, Jeong‐Ki

doi:10.1096/fj.201900866rr

Cited by 13 publications

(3 citation statements)

References 58 publications

(252 reference statements)

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“…For instance, it has been shown that NTN4 accelerates wound healing and decreases inflammation in the cornea [ 11 ]. On the contrary, the absence of NTN4 modulates pathological angiogenesis in the ischemic retina [ 6 , 9 , 12 ] and alters vascular architecture and immune cell turnover in the adult mouse retina [ 13 ]. However, these studies are limited to a few models and do not always reflect human pathology.…”

Section: Introductionmentioning

confidence: 99%

Anti-Inflammatory Role of Netrin-4 in Diabetic Retinopathy

Crespo-Garcia

Reichhart

Kociok

et al. 2021

IJMS

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Diabetic retinopathy is characterized by dysfunction of the retinal vascular network, combined with a persistent low-grade inflammation that leads to vision-threatening complications. Netrin-4 (NTN4) is a laminin-related secreted protein and guidance cue molecule present in the vascular basal membrane and highly expressed in the retina. A number of studies inferred that the angiogenic abilities of NTN4 could contribute to stabilize vascular networks and modulate inflammation. Analyzing human specimens, we show that NTN4 and netrin receptors are upregulated in the diabetic retina. We further evaluated a knock-out model for NTN4 undergoing experimental diabetes induced by streptozotocin. We investigated retina function and immune cells in vivo and demonstrated that NTN4 provides a protective milieu against inflammation in the diabetic retina and prevents cytokine production.

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Section: Introductionmentioning

confidence: 99%

Anti-Inflammatory Role of Netrin-4 in Diabetic Retinopathy

Crespo-Garcia

Reichhart

Kociok

et al. 2021

IJMS

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“…A high concentration of Ntn-4 (5 µg/ml) has been found to inhibit endothelial cell proliferation and promote endothelial cell apoptosis, whereas a low concentration of Ntn-4 (100 ng/ml) exerts the opposite effect ( 31 ). The majority of previously published studies have suggested that Ntn-4 binds to the receptor, Unc5B, to promote both the proliferation and differentiation of endothelial progenitor cells and the angiogenesis of ischaemic hind limbs in mice ( 32 ), whereas the proliferation and angiogenesis of human placental endothelial cells and retinas is inhibited ( 10 , 33 , 34 ). By contrast, it has been demonstrated that the role of Ntn-4 is mediated by regulating the BM through its interaction with laminin, rather than by binding to receptors of the Ntn family ( 13 , 15 ).…”

Section: Discussionmentioning

confidence: 99%

RNA‑binding protein quaking 5 inhibits the progression of non‑small cell lung cancer by upregulating netrin‑4 expression

Wu,

Liu,

Pang

et al. 2023

Oncol Rep

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It was recently reported that netrin-4 (Ntn-4), a component of the extracellular matrix, when downregulated, is involved in the progression of several types of cancer, including breast cancer, colorectal tumours, neuroblastoma and gastric cancer. In the present study, the level of Ntn-4 was examined in a public non-small cell lung cancer (NSCLC) dataset from the Netherlands Cancer Institute. This analysis revealed that the mRNA expression level of Ntn-4 was lower in the samples of patients with NSCLC compared with that in the control samples. Consistent with the mRNA level, the protein level of Ntn-4 was also found to be decreased in NSCLC cells. However, both the function of Ntn-4 and the underlying mechanisms of Ntn-4 downregulation in NSCLC have yet to be fully elucidated. As was anticipated, the overexpression of Ntn-4 led to a marked decrease in the proliferation, migration and invasion of NSCLC cells. Notably, RNA-binding protein quaking 5 (Qki-5) was found to exhibit antitumor activity in lung cancer, not only by enhancing the level of Ntn-4 by binding to Ntn-4 mRNA, but also by suppressing the proliferation, invasion and migration of NSCLC cells. However, Qki-5 is known to be frequently downregulated in NSCLC. Moreover, the knockdown of Ntn-4 was found to reverse the suppressive effects of Qki-5 on NSCLC progression both in vitro and in vivo . Taken together, the findings of the present study demonstrate that Ntn-4 is able to suppress the progression of NSCLC, and that the level of Ntn-4 can be regulated by Qki-5. Therefore, Ntn-4 may be a novel diagnostic and therapeutic target for the treatment of NSCLC.

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“…The wound healing process in chronic pressure ulcers is complicated, involving remodeling and deposition of extracellular matrix (ECM), cell proliferation, inflammation, and angiogenesis [ 3 , 4 ]. Meanwhile, endothelial progenitor cells (EPCs), which originated from the bone marrow upon acute injury, participate in the neovascularization [ 5 ]. The fluid EPCs numbers are applied as a marker of endothelial disorder or remedy several diseases [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

Sonic hedgehog signaling promotes angiogenesis of endothelial progenitor cells to improve pressure ulcers healing by PI3K/AKT/eNOS signaling

Wang,

Zhan,

Wang

et al. 2023

Aging

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Background: Pressure ulcer is a severe disease in the paralyzed and aging populations. Endothelial progenitor cells (EPCs) are able to regulate ulcer healing by modulating angiogenesis, but the molecular mechanism is still obscure. Sonic hedgehog (SHH) signaling contributes to angiogenesis in various diseases and has been identified to modulate EPCs function. Here, we aimed to explore the significance of SHH signaling in EPCs function during pressure ulcers. Methods: The EPCs were isolated and characterized by the expression of DiI-acLDL and bind fluorescein iso-thiocyanate UEA-1. Cell proliferation was detected by cell counting kit 8 (CCK-8). The DiI-acLDL and bind fluorescein iso-thiocyanate UEA-1 were analyzed by immunofluorescent analysis. The angiogenesis of EPCs was analyzed by tube formation assay. The pressure ulcers rat model was constructed, the wound injury was analyzed by H&E staining and angiogenesis was analyzed by the accumulation of CD31 based on immunofluorescent analysis. Results: The expression of patched-1 and Gli-1 was enhanced by SHH activator SAG but reduced by SHH inhibitor cyclopamine in the EPCsThe PI3K, Akt, eNOS expression and the Akt phosphorylation were induced by SAG, while the treatment of cyclopamine presented a reversed result. The proliferation and migration of EPCs were enhanced by SAG but repressed by cyclopamine or PI3K/AKT/eNOS signaling inhibitor Y294002, in which the co-treatment of Y294002 could reverse the effect of SAG. Conclusions: Thus, we found that SHH signaling activated angiogenesis properties of EPCs to improve pressure ulcers healing by PI3K/AKT/eNOS signaling. SHH signaling may serve as the potential target for attenuating pressure ulcers.

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Ischemia‐induced Netrin‐4 promotes neovascularization through endothelial progenitor cell activation via Unc‐5 Netrin receptor B

Cited by 13 publications

References 58 publications

Anti-Inflammatory Role of Netrin-4 in Diabetic Retinopathy

Anti-Inflammatory Role of Netrin-4 in Diabetic Retinopathy

RNA‑binding protein quaking 5 inhibits the progression of non‑small cell lung cancer by upregulating netrin‑4 expression

Sonic hedgehog signaling promotes angiogenesis of endothelial progenitor cells to improve pressure ulcers healing by PI3K/AKT/eNOS signaling

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