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Role of Erythropoietin Receptor Signaling in Macrophages or Choroidal Endothelial Cells in Choroidal Neovascularization.

ABSTRACT: Erythropoietin (EPO) has been proposed to reduce the progression of atrophic age-related macular degeneration (AMD) due to its potential role in neuroprotection. However, overactive EPO receptor (EPOR) signaling increased laser-induced choroidal neovascularization (CNV) and choroidal macrophage number in non-lasered mice, which raised the question of whether EPOR signaling increased CNV through the recruitment of macrophages to the choroid that released pro-angiogenic factors or through direct angiogenic effects on endothelial cells. In this study, we addressed the hypothesis that EPOR signaling increased CNV by direct effects on macrophages or endothelial cells. We used tamoxifen-inducible macrophage-specific or endothelial cell-specific EPOR knockout mice in the laser-induced CNV model, and cultured choroidal endothelial cells isolated from adult human donors. We found that macrophage-specific knockout of EPOR influenced laser-induced CNV in females only, whereas endothelial-specific knockout of EPOR reduced laser-induced CNV in male mice only. In cultured human choroidal endothelial cells, knockdown of EPOR reduced EPO-induced signal transducer and activator of transcription 3 (STAT3) activation. Taken together, our findings suggest that EPOR signaling in macrophages or choroidal endothelial cells regulates the development of CNV in a sex-dependent manner. Further studies regarding the role of EPO-induced signaling are required to assess EPO safety and to select or develop appropriate therapeutic approaches.

SUBMITTER: Ramshekar A

PROVIDER: S-EPMC9312702 | biostudies-literature |

REPOSITORIES: biostudies-literature

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CSF1/CSF1R-mediated Crosstalk Between Choroidal Vascular Endothelial Cells and Macrophages Promotes Choroidal Neovascularization.

Project description:PurposeThis study examined the role of the CSF1/CSF1Raxis in the crosstalk between choroidal vascular endothelial cells (CVECs) and macrophages during the formation of choroidal neovascularization (CNV).MethodsQuantitative reverse transcriptase (QRT)-PCR, Western blot and ELISA measured the production and release of CSF1 from human choroidal vascular endothelial cells (HCVECs) under hypoxic conditions. Western blot detected CSF1 released from HCVECs under hypoxic conditions that activated the PI3K/AKT/FOXO1 axis in human macrophages via binding to CSF1R. Transwell migration assay, qRT-PCR, and Western blot detected the effect of CSF1 released from HCVECs on macrophage migration and M2 polarization via the CSF1R/PI3K/AKT/FOXO1 pathway. Incorporation of 5-ethynyl-20-deoxyuridine, transwell migration, and tube formation assays detected the effects of CSF1/CSF1R on the behaviors of HCVECs. Fundus fluorescein angiography (FFA), indocyanine green angiography (ICGA), and immunofluorescence detected the effect of blockade of CSF1/CSF1R on mouse laser-induced CNV. Color fundus photograph, ICGA, and FFA detected CNV lesions in neovascular AMD (nAMD) patients. ELISA detected CSF1 and CSF1R in the aqueous humor of age-related cataract and nAMD patients.ResultsCSF1 released from HCVECs under hypoxic conditions activated the PI3K/AKT/FOXO1 axis in human macrophages via binding to CSF1R, promoting macrophage migration and M2 polarization via up-regulation of the CSF1R/PI3K/AKT/FOXO1 pathway. Human macrophages promoted the proliferation, migration, and tube formation of HCVECs in a CSF1/CSFR1-dependent manner under hypoxic conditions. CSF1/CSF1R blockade ameliorated the formation of mouse laser-induced CNV. CSF1 and CSF1R were increased in the aqueous humor of nAMD patients.ConclusionsOur results affirmed the crucial role of CSF1/CSF1R in boosting the formation of CNV and offered potential molecular targets for the treatment of nAMD.

| S-EPMC7995352 | biostudies-literature

An angiogenic role for the aryl hydrocarbon receptor in choroidal neovascularization

Project description:We report that decreased expression and activity of AhR exacerbates murine neovascular age-related macular degeneration, and increases cell migration and tube formation. The mechanism involves increased expression of pro-angiogenic mediators and altered matrix degradation. The results of our study suggest that the AhR signaling pathway may be important in multiple AMD related pathways. Gene expression analysis in the retinal pigment epithelium (RPE)-choroid tissue from AhR knockout mice contrasted against wild-type age-matched controls.

2015-01-01 | E-GEOD-56983 | biostudies-arrayexpress

Fruquintinib inhibits VEGF/VEGFR2 axis of choroidal endothelial cells and M1-type macrophages to protect against mouse laser-induced choroidal neovascularization.

Project description:Wet age-related macular degeneration, which is characterized by choroidal neovascularization (CNV) and induces obvious vision loss. Vascular endothelial growth factor (VEGF) family member VEGF-A (also named as VEGF) and its receptor VEGFR2 contribute to the pathogenesis of CNV. Choroidal endothelial cells (CECs) secret C-C motif chemokine ligand 2 (CCL2), which attracts macrophages to CNV lesion and promotes macrophage M1 polarization. Accordingly, infiltrating macrophages secret inflammatory cytokines to promote CNV. In vivo, intravitreal injection of fruquintinib (HMPL-013), an antitumor neovascularization drug, alleviated mouse CNV formation without obvious ocular toxicity. Meanwhile, HMPL-013 inhibited VEGF/VEGFR2 binding in CECs and macrophages, as well as macrophage M1 polarization. In vitro, noncontact coculture of human choroidal vascular endothelial cells (HCVECs) and macrophages under hypoxia conditions was established. HMPL-013 downregulated VEGF/VEGFR2/phosphoinositide-3-kinase/protein kinase B (AKT)/nuclear factor kappa B pathway and CCL2 secretion in HCVECs, as well as VEGF/VEGFR2-induced macrophage M1 polarization under hypoxia condition. In addition, HMPL-013 inhibited HCEVC derived CCL2-induced macrophage migration and M1 polarization, along with macrophage M1 polarization-induced HCVECs proliferation, migration, and tube formation. Altogether, HMPL-013 alleviated CNV formation might via breaking detrimental cross talk between CECs and macrophages.

| S-EPMC7695853 | biostudies-literature

Choroidal Neovascularization: Mechanisms of Endothelial Dysfunction.

Project description:Many conditions affecting the heart, brain, and even the eyes have their origins in blood vessel pathology, underscoring the role of vascular regulation. In age-related macular degeneration (AMD), there is excessive growth of abnormal blood vessels in the eye (choroidal neovascularization), eventually leading to vision loss due to detachment of retinal pigmented epithelium. As the advanced stage of this disease involves loss of retinal pigmented epithelium, much less attention has been given to early vascular events such as endothelial dysfunction. Although current gold standard therapy using inhibitors of vascular endothelial growth factor (VEGF) have achieved initial successes, some drawbacks include the lack of long-term restoration of visual acuity, as well as a subset of the patients being refractory to existing treatment, alluding us and others to hypothesize upon VEGF-independent mechanisms. Against this backdrop, we present here a nonexhaustive review on the vascular underpinnings of AMD, implications with genetic and systemic factors, experimental models for studying choroidal neovascularization, and interestingly, on both endothelial-centric pathways and noncell autonomous mechanisms. We hope to shed light on future research directions in improving vascular function in ocular disorders.

| S-EPMC6895252 | biostudies-literature

Active Rap1-mediated inhibition of choroidal neovascularization requires interactions with IQGAP1 in choroidal endothelial cells.

Project description:Neovascular age-related macular degeneration (nAMD) is a leading cause of blindness. The pathophysiology involves activation of choroidal endothelial cells (CECs) to transmigrate the retinal pigment epithelial (RPE) monolayer and form choroidal neovascularization (CNV) in the neural retina. The multidomain GTPase binding protein, IQGAP1, binds active Rac1 and sustains activation of CECs, thereby enabling migration associated with vision-threatening CNV. IQGAP1 also binds the GTPase, Rap1, which when activated reduces Rac1 activation in CECs and CNV. In this study, we tested the hypothesis that active Rap1 binding to IQGAP1 is necessary and sufficient to reduce Rac1 activation in CECs, and CNV. We found that pharmacologic activation of Rap1 or adenoviral transduction of constitutively active Rap1a reduced VEGF-mediated Rac1 activation, migration, and tube formation in CECs. Following pharmacologic activation of Rap1, VEGF-mediated Rac1 activation was reduced in CECs transfected with an IQGAP1 construct that increased active Rap1-IQGAP1 binding but not in CECs transfected with an IQGAP1 construct lacking the Rap1 binding domain. Specific knockout of IQGAP1 in endothelial cells reduced laser-induced CNV and Rac1 activation in CNV lesions, but pharmacologic activation of Rap1 did not further reduce CNV compared to littermate controls. Taken together, our findings provide evidence that active Rap1 binding to the IQ domain of IQGAP1 is sufficient to interfere with active Rac1-mediated CEC activation and CNV formation.

| S-EPMC8238370 | biostudies-literature

Monocyte-Derived Macrophages Are Necessary for Beta-Adrenergic Receptor-Driven Choroidal Neovascularization Inhibition.

Project description:Purpose:Beta-adrenergic receptor (AR) antagonists, like propranolol, inhibit angiogenesis in multiple ocular conditions through an unknown mechanism. We previously showed that propranolol reduces choroidal neovascularization (CNV) by decreasing interleukin-6 levels. Since macrophages are one of the central producers of interleukin-6, we examined whether macrophages are required for propranolol-driven inhibition of choroidal angiogenesis. Methods:We tested the anti-angiogenic properties of propranolol in the choroidal sprouting assay and the laser-induced CNV model. Bone marrow-derived monocytes (BMDMs) were added to the choroidal sprouting assay and Ccr2-/- mice were subjected to laser-induced CNV. Multi-parameter flow cytometry was performed to characterize the ocular mononuclear phagocyte populations after laser injury and during propranolol treatment. Results:Propranolol reduced choroidal angiogenesis by 41% (P < 0.001) in the choroidal sprouting assay. Similarly, propranolol decreased laser-induced CNV by 50% (P < 0.05) in female mice, with no change in males. BMDMs increased choroidal sprouting by 146% (P < 0.0001), and this effect was ablated by propranolol. Beta-AR inhibition had no effect upon laser-induced CNV area in female Ccr2-/- mice. MHCII+ and MHCII- macrophages increased 20-fold following laser treatment in wildtype mice as compared to untreated mice, and this effect was completely attenuated in lasered Ccr2-/- mice. Moreover, propranolol increased the numbers of MHCII+ and MHCII- macrophages by 1.9 (P = 0.07) and 3.1 (P < 0.05) fold in lasered female mice with no change in macrophage numbers in males. Conclusions:Our data suggest that propranolol inhibits angiogenesis through recruitment of monocyte-derived macrophages in female mice only. These data show the anti-angiogenic nature of beta-AR blocker-recruited monocyte-derived macrophages in CNV.

| S-EPMC6894922 | biostudies-literature

An angiogenic role for the aryl hydrocarbon receptor in choroidal neovascularization

2015-01-01 | GSE56983 | GEO

CD200R signaling inhibits pro-angiogenic gene expression by macrophages and suppresses choroidal neovascularization.

Project description:Macrophages are rapidly conditioned by cognate and soluble signals to acquire phenotypes that deliver specific functions during inflammation, wound healing and angiogenesis. Whether inhibitory CD200R signaling regulates pro-angiogenic macrophage phenotypes with the potential to suppress ocular neovascularization is unknown. CD200R-deficient bone marrow derived macrophages (BMM?) were used to demonstrate that macrophages lacking this inhibitory receptor exhibit enhanced levels of Vegfa, Arg-1 and Il-1? when stimulated with PGE2 or RPE-conditioned (PGE2-enriched) media. Endothelial tube formation in HUVECs was increased when co-cultured with PGE2-conditioned CD200R(-/-) BMM?, and laser-induced choroidal neovascularization was enhanced in CD200R-deficient mice. In corroboration, signaling through CD200R results in the down-regulation of BMM? angiogenic and pro-inflammatory phenotypes. Translational potential of this pathway was investigated in the laser-induced model of choroidal neovascularization. Local delivery of a CD200R agonist mAb to target myeloid infiltrate alters macrophage phenotype and inhibits pro-angiogenic gene expression, which suppresses pathological angiogenesis and CNV development.

| S-EPMC3812658 | biostudies-other

Arg-Leu-Tyr-Glu Suppresses Retinal Endothelial Permeability and Choroidal Neovascularization by Inhibiting the VEGF Receptor 2 Signaling Pathway.

Project description:Vascular endothelial growth factor (VEGF) plays a pivotal role in pathologic ocular neovascularization and vascular leakage via activation of VEGF receptor 2 (VEGFR2). This study was undertaken to evaluate the therapeutic mechanisms and effects of the tetrapeptide Arg-Leu-Tyr-Glu (RLYE), a VEGFR2 inhibitor, in the development of vascular permeability and choroidal neovascularization (CNV). In cultured human retinal microvascular endothelial cells (HRMECs), treatment with RLYE blocked VEGF-A-induced phosphorylation of VEGFR2, Akt, ERK, and endothelial nitric oxide synthase (eNOS), leading to suppression of VEGFA-mediated hyper-production of NO. Treatment with RLYE also inhibited VEGF-A-stimulated angiogenic processes (migration, proliferation, and tube formation) and the hyperpermeability of HRMECs, in addition to attenuating VEGF-A-induced angiogenesis and vascular permeability in mice. The anti-vascular permeability activity of RLYE was correlated with enhanced stability and positioning of the junction proteins VE-cadherin, β-catenin, claudin-5, and ZO-1, critical components of the cortical actin ring structure and retinal endothelial barrier, at the boundary between HRMECs stimulated with VEGF-A. Furthermore, intravitreally injected RLYE bound to retinal microvascular endothelium and inhibited laser-induced CNV in mice. These findings suggest that RLYE has potential as a therapeutic drug for the treatment of CNV by preventing VEGFR2-mediated vascular leakage and angiogenesis.

| S-EPMC6720534 | biostudies-literature

Reduction of Laser-Induced Choroidal Neovascularization in Mice With Erythropoietin RNA Interference.

Project description:PurposeThe purpose of this study was to evaluate the pathological involvement of erythropoietin (EPO) in experimental choroidal neovascularization (CNV) and its association with neovascular age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV) in the Chinese population.MethodsTreatment effect of recombinant EPO protein were assessed by human umbilical vein endothelial cell (HUVEC) proliferation, migration, and tube formation, and ex vivo choroid-sprouting ability. The effect of intravitreal injection of Epo siRNA against neovascularization was evaluated in the laser-induced CNV mouse model. In addition, the association of EPO variants with neovascular AMD and PCV was determined.ResultsExogenous supplementation of EPO significantly enhanced the migration and tube formation of HUVECs and promoted ex vivo choroid sprouting in mouse retinal pigment epithelium (RPE)-choroid-sclera complex culture. In the experimental CNV mouse model, Epo expression was found to be significantly upregulated by 3.5-folds in RPE-choroid-sclera complex at day 10 after laser induction as compared to the baseline. Immunofluorescence analysis showed that Epo was mainly expressed around the vascular endothelial cells in the RPE-choroid-sclera complex. Intravitreal injection of siRNA targeting Epo reduced 40% Epo expression and 40% CNV lesion areas as compared to the scramble control. However, EPO variants were not associated with neovascular AMD nor PCV in the Chinese population.ConclusionsThis study revealed the promotion of human endothelial cell tube formation in vitro and choroid sprouting ex vivo by EPO, and the reduction of laser-induced CNV in vivo by Epo RNA interference.Translational relevanceTargeting EPO could be a potential additional treatment for CNV-related diseases.

| S-EPMC9351596 | biostudies-literature

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