Angiopoietin-1 Suppresses Choroidal Neovascularization and Vascular Leakage

Lee, Junyeop; Park, Dae Young; Park, Do Young; Park, Intae; Chang, Woo Hyok; Nakaoka, Yoshikazu; Komuro, Issei; Yoo, Ook-Joon; Koh, Gou Young

doi:10.1167/iovs.14-13897

Cited by 55 publications

(48 citation statements)

References 37 publications

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“…26 Angiopoietin 2 is upregulated by hypoxia and has been detected in surgically removed human CNV membranes. 27 Single and combined inhibition of angiopoietin 2 and VEGF-A are showing promising results in the management of ocular angiogenesis. 28 Endothelin 1 is considered a potent endogenous vasoconstrictor in small vessels, has an important regulatory role for retinal blood flow, and also may induce angiogenesis.…”

Section: Discussionmentioning

confidence: 99%

Bevacizumab Injection in Patients with Neovascular Age-Related Macular Degeneration Increases Angiogenic Biomarkers

Cabral

Lima

Mello

et al. 2018

Ophthalmology Retina

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Purpose To evaluate the expression of 19 angiogenic biomarkers in the aqueous humor before and after intravitreal bevacizumab injection (IVB) in eyes with neovascular age-related macular degeneration (AMD). Design Prospective, noncomparative, interventional case series. Participants Twenty-three eyes of 23 treatment-naïve patients with choroidal neovascularization (CNV) secondary to neovascular AMD. Methods Eyes were diagnosed with CNV secondary to neovascular AMD and were treated with 3 monthly IVBs. Aqueous humor samples were obtained by anterior chamber paracentesis at baseline and immediately before each intravitreal bevacizumab injection. Main Outcome Measures Aqueous humor levels of 19 angiogenic biomarkers (angiopoietin 2, bone morphogenetic protein 9 [BMP-9], epidermal growth factor [EGF], endoglin, endothelin 1, fibroblast growth factor [FGF]-1 and FGF-2, follistatin, granulocyte colony-stimulating factor [GCSF], heparin-binding EGF-like growth factor [HB-EGF], hepatocyte growth factor [HGF], interleukin 8, leptin, placental growth factor [PLGF], vascular endothelial growth factor [VEGF]-A, VEGF-C, VEGF-D, and tissue inhibitor of metalloproteinases [TIMP]-1 and TIMP-2) were measured. Best-corrected visual acuity (BCVA), spectral-domain OCT parameters, and intraocular pressure also were evaluated. Results Baseline aqueous VEGF-A expression was elevated in all study eyes before treatment initiation. A statistically significant decrease of VEGF-A was observed at the 1- and 2-month follow-ups. A statistically significant increased concentration was observed in 7 biomarkers: VEGF-C, angiopoietin 2, endothelin 1, follistatin, HB-EGF, HGF, and interleukin 8. The other 11 study biomarker levels (VEGF-D, BMP-9, EGF, endoglin, FGF-1, FGF-2, GCSF, leptin, PLGF, TIMP-1, and TIMP-2) did not show any significant difference during follow-up. The BCVA statistically improved significantly at 2 months. Spectral-domain OCT parameters improved significantly at all follow-ups. Mean intraocular pressure values were not statistically different during the study period. Conclusions Despite a decrease in VEGF-A, the aqueous levels of VEGF-C, angiopoietin 2, endothelin 1, follistatin, HB-EGF, HGF, and interleukin 8 increased significantly after intravitreal injection of bevacizumab. These upregulated angiogenic biomarkers may represent new therapeutic targets in exudative AMD.

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Section: Discussionmentioning

confidence: 99%

Bevacizumab Injection in Patients with Neovascular Age-Related Macular Degeneration Increases Angiogenic Biomarkers

Cabral

Lima

Mello

et al. 2018

Ophthalmology Retina

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“…Inducible ubiquitous or photoreceptor restricted expression of Ang2 or VEGF demonstrated that Ang2 stimulated retinal neovascularization (NV) in concert with VEGF, but induced vessel regression when VEGF level was low [113]. In contrast, transgenic expression of Ang1 prevented VEGF-induced NV and exudative retinal detachment in VEGF/tet/opsin mice, but did not affect established retinal and choroidal NV [114–116]. Thus, ectopic Ang1 makes ECs less responsive to VEGF-induced signals, whereas the sensitivity of ocular vasculature to Ang2 is determined by the VEGF/Ang2 ratio and additional factors, which may include integrins and ECM components [117].…”

Section: Ang–tie System In Vascular Diseasesmentioning

confidence: 99%

Angiopoietin–Tie signalling in the cardiovascular and lymphatic systems

Eklund¹,

Kangas²,

2016

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Endothelial cells that form the inner layer of blood and lymphatic vessels are important regulators of vascular functions and centrally involved in the pathogenesis of vascular diseases. In addition to the vascular endothelial growth factor (VEGF) receptor pathway, the angiopoietin (Ang)–Tie system is a second endothelial cell specific ligand–receptor signalling system necessary for embryonic cardiovascular and lymphatic development. The Ang–Tie system also regulates postnatal angiogenesis, vessel remodelling, vascular permeability and inflammation to maintain vascular homoeostasis in adult physiology. This system is implicated in numerous diseases where the vasculature has an important contribution, such as cancer, sepsis, diabetes, atherosclerosis and ocular diseases. Furthermore, mutations in the TIE2 signalling pathway cause defects in vascular morphogenesis, resulting in venous malformations and primary congenital glaucoma. Here, we review recent advances in the understanding of the Ang–Tie signalling system, including cross-talk with the vascular endothelial protein tyrosine phosphatase (VE-PTP) and the integrin cell adhesion receptors, focusing on the Ang–Tie system in vascular development and pathogenesis of vascular diseases.

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“…Laboratory studies largely deliver fluorescein via subcutaneous or intraperitoneal injection to identify blood-retinal-barrier compromise [13], [15], [32], [33]. Whilst this is an easy method of dye administration, it provides limited temporal information.…”

Section: Discussionmentioning

confidence: 99%

Quantitative Spatial and Temporal Analysis of Fluorescein Angiography Dynamics in the Eye

et al. 2014

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PurposeWe describe a novel approach to analyze fluorescein angiography to investigate fluorescein flow dynamics in the rat posterior retina as well as identify abnormal areas following laser photocoagulation.MethodsExperiments were undertaken in adult Long Evans rats. Using a rodent retinal camera, videos were acquired at 30 frames per second for 30 seconds following intravenous introduction of sodium fluorescein in a group of control animals (n = 14). Videos were image registered and analyzed using principle components analysis across all pixels in the field. This returns fluorescence intensity profiles from which, the half-rise (time to 50% brightness), half-fall (time for 50% decay) back to an offset (plateau level of fluorescence). We applied this analysis to video fluorescein angiography data collected 30 minutes following laser photocoagulation in a separate group of rats (n = 7).ResultsPixel-by-pixel analysis of video angiography clearly delineates differences in the temporal profiles of arteries, veins and capillaries in the posterior retina. We find no difference in half-rise, half-fall or offset amongst the four quadrants (inferior, nasal, superior, temporal). We also found little difference with eccentricity. By expressing the parameters at each pixel as a function of the number of standard deviation from the average of the entire field, we could clearly identify the spatial extent of the laser injury.ConclusionsThis simple registration and analysis provides a way to monitor the size of vascular injury, to highlight areas of subtle vascular leakage and to quantify vascular dynamics not possible using current fluorescein angiography approaches. This can be applied in both laboratory and clinical settings for in vivo dynamic fluorescent imaging of vasculature.

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Angiopoietin-1 Suppresses Choroidal Neovascularization and Vascular Leakage

Abstract: Ang1 supplementation can be established as a therapeutic strategy to suppress the CNV formation and vascular leakage by inhibiting the recruitment of angiogenic macrophages and tightening the endothelial junctions.

Cited by 55 publications

References 37 publications

Bevacizumab Injection in Patients with Neovascular Age-Related Macular Degeneration Increases Angiogenic Biomarkers

Bevacizumab Injection in Patients with Neovascular Age-Related Macular Degeneration Increases Angiogenic Biomarkers

Angiopoietin–Tie signalling in the cardiovascular and lymphatic systems

Quantitative Spatial and Temporal Analysis of Fluorescein Angiography Dynamics in the Eye

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