VEGFR1 signaling in retinal angiogenesis and microinflammation

Uemura, Akiyoshi; Fruttiger, Marcus; D’Amore, Patricia A.; Falco, Sandro De; Joussen, Antonia M.; Sennlaub, Florian; Brunck, Lynne R.; Johnson, Kristian; Lambrou, George N.; Rittenhouse, Kay D.; Langmann, Thomas

doi:10.1016/j.preteyeres.2021.100954

Cited by 190 publications

(148 citation statements)

References 389 publications

(526 reference statements)

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“…Advanced glycation end-products or glycation proteins can induce the release of pathophysiological substances such as IL-6, IL-8, MCP-1, ICAM-1, and IP-10 in conditions such as diabetic retinopathy [ 31 ]. In addition, microinflammation can cause diabetic retinopathy mediated by circulating monocytes, tissue-resident macrophages, and monocyte-derived inflammatory macrophages [ 32 ]. Patients with severe diabetes mellitus sometimes have accompanying iritis clinically, with hyperpermeability due to impairment of blood aqueous humor barrier due to damage of endothelial cells in capillary vessels.…”

Section: Discussionmentioning

confidence: 99%

Risk factors for emerging intraocular inflammation after intravitreal brolucizumab injection for age-related macular degeneration

2021

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Purpose To analyze the risk factors associated with emerging intraocular inflammation (IOI) after intravitreal brolucizumab injection (IVBr) to treat age-related macular degeneration (AMD). Methods This study included 93 eyes of 90 patients. The incidence of emerging IOI was analyzed. The patients were classified into IOI or non-IOI groups, and background clinical characteristics in each group were compared. Results IOI occurred in 14 eyes of 14 cases (16%; five women, nine men [5:9]; IOI group) after IVBr; contrastingly, no IOI occurred in 76 patients (10 women, 66 men [10:66]; non-IOI group). The mean ages in IOI and non-IOI groups were 79.4 ± 8.1 and 73.8 ± 8.9 years old, respectively, and the average age in the IOI group was significantly higher than that in the non-IOI group (P = 0.0425). In addition, the percentages of females in the IOI and non-IOI groups were 43% and 13%, respectively, and IOI occurred predominantly in females (odds ratio: 4.95, P = 0.0076). Moreover, the prevalence of diabetes in the IOI and non-IOI groups was 64% and 32%, respectively, with a significant difference (odds ratio: 3.90, P = 0.0196). In contrast, the prevalence of hypertension in the IOI and non-IOI groups was 36% and 57%, respectively, with no significant difference (P = 0.15). Conclusion The comparison of clinical profiles of IOI or non-IOI cases in IVBr treatment for AMD suggests that the risk factors for IOI are old age, female sex, and history of diabetes; however, IOI with vasculitis or vascular occlusion in this cohort does not seem to cause severe visual impairment. Further studies are required to investigate potential risk factors for IOI.

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Section: Discussionmentioning

confidence: 99%

Risk factors for emerging intraocular inflammation after intravitreal brolucizumab injection for age-related macular degeneration

2021

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“…Moreover, we observed that the relationship between microvascular parameters and OPL-ONL thickness in the fovea was exclusively present in PD patients, even though no significant thickness changes were detected between PD patients and controls in this area. It might be that the activation of VEGF receptor could not only promote pro-angiogenic effects, but also a microinflammation of the outer layers ( Uemura et al, 2021 ). However, the mechanistic basis of microvascular retinal changes cannot be inferred from clinical studies.…”

Section: Discussionmentioning

confidence: 99%

Foveal Remodeling of Retinal Microvasculature in Parkinson’s Disease

et al. 2021

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BackgroundRetinal microvascular alterations have been previously described in Parkinson’s disease (PD) patients using optical coherence tomography angiography (OCT-A). However, an extensive description of retinal vascular morphological features, their association with PD-related clinical variables and their potential use as diagnostic biomarkers has not been explored.MethodsWe performed a cross-sectional study including 49 PD patients (87 eyes) and 40 controls (73 eyes). Retinal microvasculature was evaluated with Spectralis OCT-A and cognitive status with Montreal Cognitive Assessment. Unified PD Rating Scale and disease duration were recorded in patients. We extracted microvascular parameters from superficial and deep vascular plexuses of the macula, including the area and circularity of foveal avascular zone (FAZ), skeleton density, perfusion density, vessel perimeter index, vessel mean diameter, fractal dimension (FD) and lacunarity using Python and MATLAB. We compared the microvascular parameters between groups and explored their association with thickness of macular layers and clinical outcomes. Data were analyzed with General Estimating Equations (GEE) and adjusted for age, sex, and hypertension. Logistic regression GEE models were fitted to predict diagnosis of PD versus controls from microvascular, demographic, and clinical data. The discrimination ability of models was tested with receiver operating characteristic curves.ResultsFAZ area was significantly smaller in patients compared to controls in superficial and deep plexuses, whereas perfusion density, skeleton density, FD and lacunarity of capillaries were increased in the foveal zone of PD. In the parafovea, microvascular parameters of superficial plexus were associated with ganglion cell-inner plexiform layer thickness, but this was mainly driven by PD with mild cognitive impairment. No such associations were observed in controls. FAZ area was negatively associated with cognition in PD (non-adjusted models). Foveal lacunarity, combined with demographic and clinical confounding factors, yielded an outstanding diagnostic accuracy for discriminating PD patients from controls.ConclusionParkinson’s disease patients displayed foveal microvascular alterations causing an enlargement of the vascular bed surrounding FAZ. Parafoveal microvascular alterations were less pronounced but were related to inner retinal layer thinning. Retinal microvascular abnormalities helped discriminating PD from controls. All this supports OCT-A as a potential non-invasive biomarker to reveal vascular pathophysiology and improve diagnostic accuracy in PD.

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“…This increase in number is a consequence of microglia activation, as previously reported in other retinal and systemic diseases. In particular, VEGF overexpression, due to the mutation of pVHL, might contribute to induce the activation of microglia in VHL patients [ 1 , 2 , 3 , 4 , 5 , 6 , 33 , 36 , 37 , 38 , 39 , 40 ]. We therefore hypothesize that pVHL alterations determine a “pre-activation” of the resident microglia.…”

Section: Discussionmentioning

confidence: 99%

Retinal Glial Cells in Von Hippel–Lindau Disease: A Novel Approach in the Pathophysiology of Retinal Hemangioblastoma

Pilotto

Midena

Torresin

et al. 2021

Cancers

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Background: Von Hippel–Lindau (VHL) disease is a neoplastic syndrome caused by a mutation of the VHL tumor suppressor gene. Retinal hemangioblastoma (RH) is a vascularized tumor and represents the most common ocular manifestation of this disease. At the retinal level, VHL protein is able to regulate tumor growth, angiogenic factors, and neuroinflammation, probably stimulating retinal glial cells. The aim of the present study was to analyze in vivo the optical coherence tomography (OCT) biomarkers of retinal macroglia and microglia in a cohort of VHL patients. Methods: The mean thicknesses of macular retinal nerve fiber layer (mRNFL), ganglion cell layer (GCL), and peripapillary retinal nerve fiber layer (pRNFL) were measured with OCT as biomarkers of retinal macroglia. OCT images were also analyzed to detect and quantify hyperreflective retinal foci (HRF), a biomarker of retinal activated microglia. Results: 61 eyes of 61 VHL patients (22 eyes (36.07%) with peripheral RH and 39 eyes (63.93%) without RH) and 28 eyes of 28 controls were evaluated. pRNFL was thinner in VHL patients (p < 0.05) and in VHL without RH (p < 0.01) compared to controls, and thicker in VHL patients with RH than in those without RH (p < 0.05). The thickness of mRNFL (p < 0.0001) and GCL (p < 0.05) was reduced in VHL patients and in VHL without RH compared to controls, whereas mRNFL (p < 0.0001) and GCL (p < 0.05) were increased in VHL patients with RH compared to those without RH. HRF were significantly higher in number in VHL patients and in VHL without RH, than in controls, and significantly lower (p < 0.05) in the eyes of VHL patients with RH, than in those without RH. Conclusions: The OCT analysis, which detects and allows to quantify the biomarkers of retinal microglia (HRF) and macroglia (pRNFL, mRNFL and GCL), showed a different behavior of these two retinal glial cells populations in VHL patients, related to the presence or absence of peripheral RH. These data allow to hypothesize a novel pathophysiologic pathway of retinal hemangioblastoma in VHL disease.

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VEGFR1 signaling in retinal angiogenesis and microinflammation

Cited by 190 publications

References 389 publications

Risk factors for emerging intraocular inflammation after intravitreal brolucizumab injection for age-related macular degeneration

Risk factors for emerging intraocular inflammation after intravitreal brolucizumab injection for age-related macular degeneration

Foveal Remodeling of Retinal Microvasculature in Parkinson’s Disease

Retinal Glial Cells in Von Hippel–Lindau Disease: A Novel Approach in the Pathophysiology of Retinal Hemangioblastoma

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