Flt3 Regulation in the Mononuclear Phagocyte System Promotes Ocular Neovascularization

Gao, Yushuo; Zhong, Yisheng; Zhu, Yanji; Demetriades, Anna M.; Cai, Yuanlong; Shen, Jikui; Lü, Qing; Shen, Xi; Xie, Bing

doi:10.1155/2018/2518568

Cited by 3 publications

(4 citation statements)

References 59 publications

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“…Flt3 −/− mice and intravitreal pharmacologic Flt3 blockade were previously shown to inhibit laser-induced CNV by ~ 40%, which we were not able to replicate 15 . The pharmacologic Flt3 inhibitor AC220 is specific at nanomolar levels, but the authors used 0.1–10 mg/ml (0.18–18 mM).…”

Section: Discussioncontrasting

confidence: 78%

Dendritic cells play no significant role in the laser-induced choroidal neovascularization model

Droho

Perlman

Lavine

2021

Sci Rep

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Age-related macular degeneration (AMD) is genetically associated with complement. Dendritic cells (DCs) play key roles during innate and adaptive immunity, and express complement components and their receptors. We investigated ocular DC heterogeneity and the role of DCs in the laser-induced choroidal neovascularization (CNV) model. In order to determine the function of DCs, we used two models of DC deficiency: the Flt3−/− and Flt3l−/− mouse. We identified three types of ocular DCs: plasmacytoid DC, classical DC-1, and classical DC-2. At steady-state, classical DCs were found in the iris and choroid but were not detectable in the retina. Plasmacytoid DCs existed at very low levels in iris, choroid, and retina. After laser injury, the number of each DC subset was up-regulated in the choroid and retina. In Flt3−/− mice, we found reduced numbers of classical DCs at steady-state, but each DC subset equally increased after laser injury between wildtype and Flt3−/− mice. In Flt3l−/− mice, each DC subsets was severely reduced after laser injury. Neither Flt3−/− or Flt3l−/− mice demonstrated reduced CNV area compared to wildtype mice. DCs do not play any significant role during the laser-induced CNV model of neovascular AMD.

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Section: Discussioncontrasting

confidence: 78%

Dendritic cells play no significant role in the laser-induced choroidal neovascularization model

Droho

Perlman

Lavine

2021

Sci Rep

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“…In mice, retinal expression of Flt3 is upregulated in ischemic conditions . In addition, mice lacking Flt3 show markedly reduced angiogenesis .…”

Section: Discussionmentioning

confidence: 99%

“…In mice, retinal expression of Flt3 is upregulated in ischemic conditions . In addition, mice lacking Flt3 show markedly reduced angiogenesis . As such, we speculate that gilteritinib, a highly selective FLT3 inhibitor, may impair the retina’s normal response to a transitory ischemic state.…”

Section: Discussionmentioning

confidence: 99%

Acute Macular Neuroretinopathy Associated With an Oral FLT3 Inhibitor

et al. 2020

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the office 3 weeks later, on her return from a cruise. Her visual acuity was 20/200 OU. An anterior segment examination was clinically significant for keratic precipitates. Posteriorly, minimal vitreous cells were noted, with clinically significant boxcarring of the retinal arteries (Figure 1). Fluorescein angiography was performed. Early-phase angiogram images are notable for vascular pruning and arterial and venous filling defects (Figure 2). Retinal ischemia with nonperfusion and late disc leakage were noted on later images of the angiogram (Figure 2). A vitreous sample was taken and sent for a Gram stain, bacterial and fungal cultures, and a viral polymerase chain reaction. All had negative findings. Her left eye was unremarkable.This constellation of findings on examination and angiography was consistent with an occlusive retinal vasculitis. She started receiving difluprednate 4 times a day and 40 mg of prednisone per day, without visual improvement at a 2-week follow-up. She subsequently tapered off of both drugs.This was a case of occlusive retinal vasculitis associated with intravitreal administration of brolucizumab in the setting of neovascular age-related macular degeneration. Since brolucizumab was approved for use in the treatment of neovascular age-related macular degeneration in October 2019, there have been reports of clinically significant intraocular inflammation and occlusive retinal vasculitis. The incidence of these events in clinical practice remains unknown at this time, to my knowledge. However, in a phase 3 clinical trial, 1 brolucizumab had an overall 4.4% incidence of intraocular inflammation, with 6 patients diagnosed with a retinal artery occlusion, embolism, or thrombosis. Although it is impossible to confirm the association of this occlusive vasculitis with the medication, this patient's temporal association of administration of the drug with visual acuity loss is notable.

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“…* * * P < 0.005 vs. the negative control group; ## P < 0.01 and ### P < 0.005 vs. the control group; NS, not significant. Journal of Ophthalmology laser-induced CNV [51]. Whether CBZ alleviates CNV progression via inhibiting the phosphorylation of FLT3 needs further exploration.…”

Section: Journal Of Ophthalmologymentioning

confidence: 99%

Cabozantinib, a Multityrosine Kinase Inhibitor of MET and VEGF Receptors Which Suppresses Mouse Laser-Induced Choroidal Neovascularization

Zhang

Zhu

Xie

et al. 2020

Journal of Ophthalmology

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Choroidal neovascularization (CNV) is a leading cause of blindness in the elderly in developed countries and is particularly associated with age-related macular degeneration (AMD). Cabozantinib (CBZ) hinders the activation of multiple receptor tyrosine kinases involved in tumor angiogenesis, such as hepatocyte growth factor receptor (MET) and vascular endothelial growth factor receptor 2 (VEGFR2). We aimed to investigate the role and mechanism of CBZ in a mouse laser-induced CNV model. In zebrafish embryos, CBZ perturbed intersegmental vessel (ISV) formation without obvious neurodevelopment impairment. In the mouse laser-induced CNV model, phosphorylated hepatocyte growth factor receptor (p-MET) and phosphorylated vascular endothelial growth factor receptor 2 (p-VEGFR2) were increased in the CNV region. CBZ intravitreal injection or oral gavage alleviated CNV leakage and the CNV lesion area without obvious intraocular toxicity, as well as disturbed the phosphorylation of MET and VEGFR2. Additionally, CBZ downregulated the expression of the hepatocyte growth factor (HGF) with no effect on the expression of the vascular endothelial growth factor (VEGF). CBZ downregulated HGF, p-MET, and p-VEGFR2 expressions in vitro, as well as inhibited the proliferation, migration, and tube formation of b-End3 cells. In summary, CBZ alleviates mouse CNV formation possibly via inhibiting the activation of MET and VEGFR2. The findings provide a novel potential therapy method for CNV patients.

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Flt3 Regulation in the Mononuclear Phagocyte System Promotes Ocular Neovascularization

Cited by 3 publications

References 59 publications

Dendritic cells play no significant role in the laser-induced choroidal neovascularization model

Dendritic cells play no significant role in the laser-induced choroidal neovascularization model

Acute Macular Neuroretinopathy Associated With an Oral FLT3 Inhibitor

Cabozantinib, a Multityrosine Kinase Inhibitor of MET and VEGF Receptors Which Suppresses Mouse Laser-Induced Choroidal Neovascularization

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