Overactivation of Norepinephrine–β2-Adrenergic Receptor Axis Promotes Corneal Neovascularization

Dong, Qiaoqiao; Qi, Benxiang; Zhang, Bin; Zhuang, Xiaoyun; Chen, Shijiu; Zhou, Qingjun; Zhang, Bi Ning; Li, Suxia

doi:10.1167/iovs.64.3.20

Cited by 5 publications

(3 citation statements)

References 42 publications

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“…Several studies have reported that enhancement of OXPHOS inhibits angiogenic sprouts and extensions, whereas inhibition of OXPHOS promotes them [69][70][71][72]. Nerves could switch on EC metabolism in favor of glycolysis via releasing adrenergic and cholinergic neurotransmitters to promote angiogenesis [71,73,74]. In PNS, the upregulated glycolytic activity of SCs delays the degeneration of perturbed axons after PNI [75].…”

Section: Discussionmentioning

confidence: 99%

Enhancing intraneural revascularization following peripheral nerve injury through hypoxic Schwann-cell-derived exosomes: an insight into endothelial glycolysis

Sun,

Zeng,

et al. 2024

J Nanobiotechnol

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Background Endothelial cell (EC)-driven intraneural revascularization (INRV) and Schwann cells-derived exosomes (SCs-Exos) both play crucial roles in peripheral nerve injury (PNI). However, the interplay between them remains unclear. We aimed to elucidate the effects and underlying mechanisms of SCs-Exos on INRV following PNI. Results We found that GW4869 inhibited INRV, as well as that normoxic SCs-Exos (N-SCs-Exos) exhibited significant pro-INRV effects in vivo and in vitro that were potentiated by hypoxic SCs-Exos (H-SCs-Exos). Upregulation of glycolysis emerged as a pivotal factor for INRV after PNI, as evidenced by the observation that 3PO administration, a glycolytic inhibitor, inhibited the INRV process in vivo and in vitro. H-SCs-Exos more significantly enhanced extracellular acidification rate/oxygen consumption rate ratio, lactate production, and glycolytic gene expression while simultaneously suppressing acetyl-CoA production and pyruvate dehydrogenase E1 subunit alpha (PDH-E1α) expression than N-SCs-Exos both in vivo and in vitro. Furthermore, we determined that H-SCs-Exos were more enriched with miR-21-5p than N-SCs-Exos. Knockdown of miR-21-5p significantly attenuated the pro-glycolysis and pro-INRV effects of H-SCs-Exos. Mechanistically, miR-21-5p orchestrated EC metabolism in favor of glycolysis by targeting von Hippel-Lindau/hypoxia-inducible factor-1α and PDH-E1α, thereby enhancing hypoxia-inducible factor-1α-mediated glycolysis and inhibiting PDH-E1α-mediated oxidative phosphorylation. Conclusion This study unveiled a novel intrinsic mechanism of pro-INRV after PNI, providing a promising therapeutic target for post-injury peripheral nerve regeneration and repair. Graphical Abstract

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Section: Discussionmentioning

confidence: 99%

Enhancing intraneural revascularization following peripheral nerve injury through hypoxic Schwann-cell-derived exosomes: an insight into endothelial glycolysis

Sun,

Zeng,

et al. 2024

J Nanobiotechnol

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“…The Oxygen Induced Retinopathy (OIR) model [37], Laser-Induced Choroidal Neovascularization (L-CNV) model [38] and Suture Induced Corneal Neovascularization (S-CNV) model [39] are established pathological animal models for retinal, choroidal and corneal neovascularization, respectively. (1) In the OIR model, C57BL/6 J mouse pups at postnatal day 7 (P7) were exposed to 75% oxygen for five days, followed by intravitreally injected with AAV at P12, and then returned to room air (21% oxygen) for another five days.…”

Section: Ocular Pathological Neovascularization Modelmentioning

confidence: 99%

“…In the L-CNV model, neovascularization induced by laser penetrates the sub-retinal pigment epithelium (sub-RPE) or the subretinal space via a rupture in the Bruch membrane, primarily replicating the pathological process of choroid angiogenesis in patients afflicted with wet agerelated macular degeneration. In the S-CNV model, neovascularization induced by sutures infiltrates an otherwise transparent and devoid-of-blood-vessels cornea, closely resembling the development of neovascularization during corneal surgery, particularly in the context of corneal transplantation [39]. Therefore, we selected the aforementioned models to assess the role of AFAP1L1 in retinal pathologic angiogenesis and choroidal pathologic angiogenesis.…”

Section: Afap1l1 Regulates Ocular Neovascularization By Regulating Va...mentioning

confidence: 99%

Hypoxia-induced AFAP1L1 regulates pathological neovascularization via the YAP-DLL4-NOTCH axis

Ren,

Bai,

Ding

et al. 2023

J Transl Med

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Background Pathological neovascularization plays a pivotal role in the onset and progression of tumors and neovascular eye diseases. Despite notable advancements in the development of anti-angiogenic medications that target vascular endothelial growth factor (VEGF) and its receptors (VEGFRs), the occurrence of adverse reactions and drug resistance has somewhat impeded the widespread application of these drugs. Therefore, additional investigations are warranted to explore alternative therapeutic targets. In recent years, owing to the swift advancement of high-throughput sequencing technology, pan-cancer analysis and single-cell sequencing analysis have emerged as pivotal methodologies and focal areas within the domain of omics research, which is of great significance for us to find potential targets related to the regulation of pathological neovascularization. Methods Pan-cancer analysis and scRNA-seq data analysis were employed to forecast the association between Actin filament-associated protein 1 like 1 (AFAP1L1) and the development of tumors and endothelial cells. Tumor xenograft model and ocular pathological neovascularization model were constructed as well as Isolectin B4 (IsoB4) staining and immunofluorescence staining were used to assess the effects of AFAP1L1 on the progression of neoplasms and neovascular eye diseases in vivo. Transwell assay, wound scratch assay, tube forming assay, three-dimensional germination assay, and rhodamine-phalloidin staining were used to evaluate the impact of AFAP1L1 on human umbilical vein endothelial cells (HUVECs) function in vitro; Dual luciferase reporting, qRT-PCR and western blot were used to investigate the upstream and downstream mechanisms of pathological neovascularization mediated by AFAP1L1. Results Our investigation revealed that AFAP1L1 plays a crucial role in promoting the development of various tumors and demonstrates a strong correlation with endothelial cells. Targeted suppression of AFAP1L1 specifically in endothelial cells in vivo proves effective in inhibiting tumor formation and ocular pathological neovascularization. Mechanistically, AFAP1L1 functions as a hypoxia-related regulatory protein that can be activated by HIF-1α. In vitro experiments demonstrated that reducing AFAP1L1 levels can reverse hypoxia-induced excessive angiogenic capacity in HUVECs. The principal mechanism of angiogenesis inhibition entails the regulation of tip cell behavior through the YAP-DLL4-NOTCH axis. Conclusion In conclusion, AFAP1L1, a newly identified hypoxia-related regulatory protein, can be activated by HIF-1α. Inhibiting AFAP1L1 results in the inhibition of angiogenesis by suppressing the germination of endothelial tip cells through the YAP-DLL4-NOTCH axis. This presents a promising therapeutic target to halt the progression of tumors and neovascular eye disease.

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Inhibiting PRMT1 protects against CoNV by regulating macrophages through the FGF2/PI3K/Akt pathway

Gao,

Mao,

Zhang

et al. 2024

European Journal of Pharmacology

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Overactivation of Norepinephrine–β2-Adrenergic Receptor Axis Promotes Corneal Neovascularization

Cited by 5 publications

References 42 publications

Enhancing intraneural revascularization following peripheral nerve injury through hypoxic Schwann-cell-derived exosomes: an insight into endothelial glycolysis

Enhancing intraneural revascularization following peripheral nerve injury through hypoxic Schwann-cell-derived exosomes: an insight into endothelial glycolysis

Hypoxia-induced AFAP1L1 regulates pathological neovascularization via the YAP-DLL4-NOTCH axis

Inhibiting PRMT1 protects against CoNV by regulating macrophages through the FGF2/PI3K/Akt pathway

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