Tie2 activation promotes choriocapillary regeneration for alleviating neovascular age-related macular degeneration

Kim, Jaeryung; Park, Jang Ryul; Choi, Jeongwoon; Park, Intae; Hwang, Yoonha; Bae, Hosung; Kim, YongJoo; Choi, WooJhon; Yang, Jae‐Ho; Han, Sungwon; Chung, Tae Young; Kim, Pilhan; Kubota, Yoshiaki; Augustin, Hellmut G.; Oh, Wang‐Yuhl; Koh, Gou Young

doi:10.1126/sciadv.aau6732

Cited by 48 publications

(41 citation statements)

References 56 publications

(102 reference statements)

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“…In LCNV in mice, overexpression of Ang1 was found to suppress CNV formation and vascular leakage by inhibiting the recruitment of angiogenic macrophages and tightening the endothelial junctions 29 . Tie2 activation by Ang 2 binding and Tie2-activating antibody (ABTAA) was also reported to alleviate CNV and vascular leakage 30 . These findings indicate that Tie2 activation has a strong protective effect in an LCNV model.…”

Section: Discussionmentioning

confidence: 99%

Essential Contribution of Macrophage Tie2 Signalling in a Murine Model of Laser-Induced Choroidal Neovascularization

Yin

Zhang

Chen

et al. 2020

Sci Rep

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Wet age-related macular degeneration (AMD), which can cause progressive blindness, is characterised by choroid neovascularization (cnV) in the macular area. Although close attention has been paid to AMD, and anti-vascular endothelial growth factor (VeGf) drugs are available, its complex pathogenesis is still elusive. Tie2-expressing macrophages (TEMs) have been found to promote angiogenesis in remodel tissues and tumours. This study aimed to elucidate the role of macrophage Tie2 signalling in laser-induced cnV (LcnV). We observed that teMs were responsible for the severity of cnV. Mechanistically, TEM deletion resulted in impaired LCNV due to the suppression of inflammatory angiogenesis and the promotion of apoptosis. We also observed that teMs prevented apoptosis of b.End3 cells, but promoted their migration, proliferation and tube formation via VEGF, extracellular signal-regulated kinase (eRK) and v-akt murine thymoma viral oncogene (AKt)-dependent signalling pathways. The flow cytometry results comparing dry AMD patients and healthy controls with wet AMD patients showed that the percentage of Tie2 + CD14 + cells was higher in the wet AMD patients' peripheral blood. This study demonstrates that Tie2 expression by macrophages intensifies CNV in LcnV murine models, thereby proposing an additional intervention option to inhibit cnV. Choroidal neovascularization (CNV) is a terminal symptom of age-related macular degeneration (AMD), which is directly related to aging and chronic stress diseases 1. Inflammation plays an important role in neovascular AMD (nvAMD). It was suggested that AMD is triggered by a chronic low-grade, whole body and local inflammatory response 2. These immunity activations have been found to manifest as the activation of complement, mononuclear cell recruitment and macrophage descendants 3. Inflammatory-related genes expressed in monocytes and peripheral blood mononuclear cells have been reported in nvAMD patients 4. A significant number of macrophages have been detected in AMD in human eyes, and they modulated the formation of CNV in a laser-induced CNV (LCNV) murine model 5-7. Tie2-expressing macrophages (TEMs) are a subpopulation of macrophages. Their presence and phenotype have been confirmed in human blood 8. TEMs have been found to promote angiogenesis in remodel tissues and tumours 9. Deletion of TEMs was reported to inhibit angiogenesis in limb ischemia, hepatocellular carcinoma and tumour relapse 10-12. Furthermore, researchers have reported that, potentially, increased recruitment of TEMs plays a role in enhanced neovascularization 13,14. Macrophage Tie2-signal mediated-autophagy plays a critical role in LCNV 14. However, the actual role of TEMs in AMD is still unclear. Therefore, the present study was designed to investigate whether the mechanism for TEMs contributes to LCNV as a model of AMD. Results Accumulation of intra-choroidal teMs increased during LcnV. To study the role of TEMs in LCNV, laser injury was induced to the choroid plexus of mice. We found that the injury promoted ...

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Section: Discussionmentioning

confidence: 99%

Essential Contribution of Macrophage Tie2 Signalling in a Murine Model of Laser-Induced Choroidal Neovascularization

Yin

Zhang

Chen

et al. 2020

Sci Rep

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“…According to our results, the CNS myeloid cells expressed much lower levels of Ang2 than ECs. Furthermore, Ang2 overexpression in ECs exacerbated EAE, whereas both Ang2-blocking Ab and ABTAA, which induces Tie2 activation in ECs (16,49), ameliorated EAE. These data suggest that the EC-derived Ang2 is mainly responsible for the aggravation of neuroinflammation.…”

Section: Ang2 Blockade Attenuates Leukocyte Recruitment Into the Cnsmentioning

confidence: 95%

Angiopoietin-2 blockade ameliorates autoimmune neuroinflammation by inhibiting leukocyte recruitment into the CNS

Li¹,

Korhonen²,

Merlini³

et al. 2020

Journal of Clinical Investigation

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“…The angiopoietin-Tie2 system is essential for vascular regulation and homeostasis, and stabilizing Tie2 by delivering angiopoietin 1 can suppress neovascularization, edema, and leakage in a mouse model of CNV (Lee et al 2014). More recent work has shown that in addition to these beneficial effects in suppression of CNV and its side effects, a Tie2-activating antibody also promotes regeneration of the choriocapillaris in animal models of CNV (Kim et al 2019), suggesting this may be an exciting therapeutic target for multiple forms of choroidal disease where choriocapillaris involvement occurs.…”

Section: Effect Of Treatments For Neovascular Amd On the Choroidmentioning

confidence: 99%

Microvascular contributions to age-related macular degeneration (AMD): from mechanisms of choriocapillaris aging to novel interventions

et al. 2019

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Aging of the microcirculatory network plays a central role in the pathogenesis of a wide range of agerelated diseases, from heart failure to Alzheimer's disease. In the eye, changes in the choroid and choroidal microcirculation (choriocapillaris) also occur with age, and these changes can play a critical role in the pathogenesis of age-related macular degeneration (AMD). In order to develop novel treatments for amelioration of choriocapillaris aging and prevention of AMD, it is essential to understand the cellular and functional changes that occur in the choroid and choriocapillaris during aging. In this review, recent advances in in vivo analysis of choroidal structure and function in AMD patients and patients at risk for AMD are discussed. The pathophysiological roles of fundamental cellular and molecular mechanisms of aging including oxidative GeroScience

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Tie2 activation promotes choriocapillary regeneration for alleviating neovascular age-related macular degeneration

Abstract: Angpt-Tie2 is essential for choriocapillary maintenance, and Tie2 activation could be a therapeutic avenue for fundamental treatment of NV-AMD.

Cited by 48 publications

References 56 publications

Essential Contribution of Macrophage Tie2 Signalling in a Murine Model of Laser-Induced Choroidal Neovascularization

Essential Contribution of Macrophage Tie2 Signalling in a Murine Model of Laser-Induced Choroidal Neovascularization

Angiopoietin-2 blockade ameliorates autoimmune neuroinflammation by inhibiting leukocyte recruitment into the CNS

Microvascular contributions to age-related macular degeneration (AMD): from mechanisms of choriocapillaris aging to novel interventions

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