Activation of the Endothelin System Mediates Pathological Angiogenesis during Ischemic Retinopathy

Patel, Chintan; Narayanan, S. Priya; Zhang, Wenbo; Xu, Zhimin; Sukumari‐Ramesh, Sangeetha; Dhandapani, Krishnan M.; Caldwell, Robert W.; Caldwell, Ruth B.

doi:10.1016/j.ajpath.2014.07.012

Cited by 35 publications

(27 citation statements)

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“…Upregulation in REC but not in CEC under hypoxia supports a role for EDN1 in retinal angiogenic conditions and is consistent with previously published results (Ergul ; Patel et al. ).…”

Section: Discussionsupporting

confidence: 93%

Differential hypoxic response of human choroidal and retinal endothelial cells proposes tissue heterogeneity of ocular angiogenesis

Mammadzada

Gudmundsson

Kvanta

et al. 2016

Acta Ophthalmologica

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“…Upregulation in REC but not in CEC under hypoxia supports a role for EDN1 in retinal angiogenic conditions and is consistent with previously published results (Ergul ; Patel et al. ).…”

Section: Discussionsupporting

confidence: 93%

Differential hypoxic response of human choroidal and retinal endothelial cells proposes tissue heterogeneity of ocular angiogenesis

Mammadzada

Gudmundsson

Kvanta

et al. 2016

Acta Ophthalmologica

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“…Both ET-1 and ADMA associated strongly, and inversely, with choroidal thickness in those with CKD. ET-1 contributes to the vasoconstriction that is seen in many eye diseases (35, 36) and blocking its effects improves retinal vascular integrity (37). Thus, ET receptor antagonism, a novel therapeutic strategy currently being investigated for renoprotection in CKD (38), may also have benefits for the eye.…”

Section: Discussionmentioning

confidence: 99%

Chorioretinal thinning in chronic kidney disease links to inflammation and endothelial dysfunction

Balmforth¹,

Bragt²,

Ruijs³

et al. 2016

JCI Insight

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BACKGROUND. Chronic kidney disease (CKD) is strongly associated with cardiovascular disease and there is an established association between vasculopathy affecting the kidney and eye. Optical coherence tomography (OCT) is a novel, rapid method for high-definition imaging of the retina and choroid. Its use in patients at high cardiovascular disease risk remains unexplored.METHODS. We used the new SPECTRALIS OCT machine to examine retinal and retinal nerve fiber layer (RNFL) thickness, macular volume, and choroidal thickness in a prospective cross-sectional study in 150 subjects: 50 patients with hypertension (defined as a documented clinic BP greater than or equal to 140/90 mmHg (prior to starting any treatment) with no underlying cause identified); 50 with CKD (estimated glomerular filtration rate (eGFR) 8–125 ml/min/1.73 m2); and 50 matched healthy controls. We excluded those with diabetes. The same, masked ophthalmologist carried out each study. Plasma IL-6, TNF-α , asymmetric dimethylarginine (ADMA), and endothelin-1 (ET-1), as measures of inflammation and endothelial function, were also assessed.RESULTS. Retinal thickness, macular volume, and choroidal thickness were all reduced in CKD compared with hypertensive and healthy subjects (for retinal thickness and macular volume P < 0.0001 for CKD vs. healthy and for CKD vs. hypertensive subjects; for choroidal thickness P < 0.001 for CKD vs. healthy and for CKD vs. hypertensive subjects). RNFL thickness did not differ between groups. Interestingly, a thinner choroid was associated with a lower eGFR (r = 0.35, P <0.0001) and, in CKD, with proteinuria (r = –0.58, P < 0.001) as well as increased circulating C-reactive protein (r = –0.57, P = 0.0002), IL-6 (r = –0.40, P < 0.01), ADMA (r = –0.37, P = 0.02), and ET-1 (r = –0.44, P < 0.01). Finally, choroidal thinning was associated with renal histological inflammation and arterial stiffness. In a model of hypertension, choroidal thinning was seen only in the presence of renal injury.CONCLUSIONS. Chorioretinal thinning in CKD is associated with lower eGFR and greater proteinuria, but not BP. Larger studies, in more targeted groups of patients, are now needed to clarify whether these eye changes reflect the natural history of CKD. Similarly, the associations with arterial stiffness, inflammation, and endothelial dysfunction warrant further examination.TRIAL REGISTRATION. Registration number at www.clinicalTrials.gov: NCT02132741.SOURCE OF FUNDING. TR was supported by a bursary from the Erasmus Medical Centre, Rotterdam. JJMHvB was supported by a bursary from the Utrecht University. JRC is supported by a Rowling Scholarship. SB was supported by a Wellcome Trust funded clinical research fellowship from the Scottish Translational Medicine and Therapeutics Initiative, and by a Rowling Scholarship, at the time of this work. ND is supported by a British Heart Foundation Intermediate Clinical Research Fellowship (FS/13/30/29994).

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“…Treatment effects on vaso-obliteration and pathological angiogenesis were assessed by morphometric analysis of the avascular and neovascularization areas in retinal flat mounts after labeling with isolectin B 4 as described previously [52,53]. Immunofluorescence analysis (IFA) of the retina flat mounts was performed to assess the effects of the TREM-1-targeting treatments on the distribution of TREM-1, M-CSF and markers for inflammatory cells (CD45) and activated macrophage/microglial cells (Iba-1) in relation to RNV.…”

Section: Methodsmentioning

confidence: 99%

Blockade of TREM-1 prevents vitreoretinal neovascularization in mice with oxygen-induced retinopathy

Rojas

Caldwell

Sigalov

2018

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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In pathological retinal neovascularization (RNV) disorders, the retina is infiltrated by activated leukocytes and macrophages. Triggering receptor expressed on myeloid cells 1 (TREM-1), an inflammation amplifier, activates monocytes and macrophages and plays an important role in cancer, autoimmune and other inflammation-associated disorders. Hypoxia-inducible TREM-1 is involved in cancer angiogenesis but its role in RNV remains unclear. Here, to close this gap, we evaluated the role of TREM-1 in RNV using a mouse model of oxygen-induced retinopathy (OIR). We found that hypoxia induced overexpression of TREM-1 in the OIR retinas compared to that of the room air group. TREM-1 was observed specifically in areas of pathological RNV, largely colocalizing with macrophage colony-stimulating factor (M-CSF) and CD45- and Iba-1-positive cells. TREM-1 blockade using systemically administered first-in-class ligand-independent TREM-1 inhibitory peptides rationally designed using the signaling chain homooligomerization (SCHOOL) strategy significantly (up to 95%) reduced vitreoretinal neovascularization. The peptides were well-tolerated when formulated into lipopeptide complexes for peptide half-life extension and targeted delivery. TREM-1 inhibition substantially downregulated retinal protein levels of TREM-1 and M-CSF suggesting that TREM-1-dependent suppression of pathological angiogenesis involves M-CSF. Targeting TREM-1 using TREM-1-specific SCHOOL peptide inhibitors represents a novel strategy to treat retinal diseases that are accompanied by neovascularization including retinopathy of prematurity.

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Activation of the Endothelin System Mediates Pathological Angiogenesis during Ischemic Retinopathy

Cited by 35 publications

References 50 publications

Differential hypoxic response of human choroidal and retinal endothelial cells proposes tissue heterogeneity of ocular angiogenesis

Differential hypoxic response of human choroidal and retinal endothelial cells proposes tissue heterogeneity of ocular angiogenesis

Chorioretinal thinning in chronic kidney disease links to inflammation and endothelial dysfunction

Blockade of TREM-1 prevents vitreoretinal neovascularization in mice with oxygen-induced retinopathy

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