Reversible retinal vessel closure from VEGF-induced leukocyte plugging

Liu, Yuanyuan; Shen, Jikui; Fortmann, Seth D.; Wang, Jiangxia; Vestweber, Dietmar; Campochiaro, Peter A.

doi:10.1172/jci.insight.95530

Cited by 45 publications

(34 citation statements)

References 66 publications

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“…VEGF plays a critical role in the pathogenesis of diabetic retinopathy as well as NVAMD. Increased levels of VEGF in the retina cause leukostasis and closure of retinal vessels exacerbating retinal hypoxia 41 , which is strongly associated with progression of diabetic retinopathy 28,42 . Adult C57BL/6 mice were given an intravitreous injection of 200 ng of VEGF in each eye one week after injection of MPs containing 10 µg sunitinib or 40 µg of aflibercept in one eye and an equivalent mass of empty MPs or PBS in the fellow eye.…”

Section: Subconjunctival Sunitinib Mps Suppress Type 2 Choroidal Nvmentioning

confidence: 99%

Sustained treatment of retinal vascular diseases with self-aggregating sunitinib microparticles

Tsujinaka

Shen

et al. 2020

Nat Commun

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Neovascular age-related macular degeneration and diabetic retinopathy are prevalent causes of vision loss requiring frequent intravitreous injections of VEGF-neutralizing proteins, and under-treatment is common and problematic. Here we report incorporation of sunitinib, a tyrosine kinase inhibitor that blocks VEGF receptors, into a non-inflammatory biodegradable polymer to generate sunitinib microparticles specially formulated to self-aggregate into a depot. A single intravitreous injection of sunitinib microparticles potently suppresses choroidal neovascularization in mice for six months and in another model, blocks VEGF-induced leukostasis and retinal nonperfusion, which are associated with diabetic retinopathy progression. After intravitreous injection in rabbits, sunitinib microparticles self-aggregate into a depot that remains localized and maintains therapeutic levels of sunitinib in retinal pigmented epithelium/choroid and retina for more than six months. There is no intraocular inflammation or retinal toxicity. Intravitreous injection of sunitinib microparticles provides a promising approach to achieve sustained suppression of VEGF signaling and improve outcomes in patients with retinal vascular diseases.

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Section: Subconjunctival Sunitinib Mps Suppress Type 2 Choroidal Nvmentioning

confidence: 99%

Sustained treatment of retinal vascular diseases with self-aggregating sunitinib microparticles

Tsujinaka

Shen

et al. 2020

Nat Commun

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“…We have previously demonstrated that increased intraocular levels of VEGF increase intravascular adherent leukocytes in the retina causing leukocytic plugging of retinal vessels, however extravascular F4/80‐positive macrophages were not increased by intraocular injection of 1 µL of 6.25 mmol/L VEGF (Figure B). Conversely, intravascular leukocytes were not increased by intraocular injection of 1 µL of 6.25 mmol/L HGF (Figure A,B).…”

Section: Resultsmentioning

confidence: 86%

“…Adult C57BL/6 mice were given an intravitreous injection of 1 μL of 6.25 mmol/L HGF or 6.25 mmol/L VEGF in one eye and 1 μL of PBS in the fellow eye. Twenty‐four hours after injection, leukostasis was measured as previously described . Briefly, mice were anesthetized, the chest was opened to expose the heart, the right atrium was cut for drainage, a 27‐gauge cannula was inserted into left ventricle, and the vasculature was flushed with PBS for 3 minutes to removal all nonadherent cells.…”

Section: Methodsmentioning

confidence: 99%

“…Twenty-four hours after injection, leukostasis was measured as previously described. 32 Briefly, mice were anesthetized, the chest was opened to expose the heart, the right atrium was cut for drainage, a 27-gauge cannula was inserted into left ventricle, and the vasculature was flushed with PBS for 3 minutes to removal all nonadherent cells. Mice were then perfused over a span of 2-3 minutes with rhodamine-or FITC-labeled conA (20 µg/mL in PBS, 5 mg/kg; RL-1002 and FL-1001; Vector Labs Thermofisher).…”

Section: Measurement Of Retinal Leukostasismentioning

confidence: 99%

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Hepatocyte growth factor is upregulated in ischemic retina and contributes to retinal vascular leakage and neovascularization

et al. 2020

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In patients with macular edema due to ischemic retinopathy, aqueous levels of hepatocyte growth factor (HGF) correlate with edema severity. We tested whether HGF expression and activity in mice with oxygen‐induced ischemic retinopathy supports a role in macular edema. In ischemic retina, HGF was increased in endogenous cells and macrophages associated with retinal neovascularization (NV). HGF activator was increased in and around retinal vessels potentially providing vascular targeting. One day after intravitreous injection of HGF, VE‐cadherin was reduced and albumin levels in retina and vitreous were significantly increased indicating vascular leakage. Injection of VEGF caused higher levels of vitreous albumin than HGF, and co‐injection of both growth factors caused significantly higher levels than either alone. HGF increased the number of macrophages on the retinal surface, which was blocked by anti‐c‐Met and abrogated in chemokine (C‐C motif) ligand 2 (CCL2)−/− mice. Injection of anti‐c‐Met significantly decreased leakage within 24 hours and after 5 days it reduced retinal NV in mice with ischemic retinopathy, but had no effect on choroidal NV. These data indicate that HGF is a pro‐permeability, pro‐inflammatory, and pro‐angiogenic factor and along with its activator is increased in ischemic retina providing support for a potential role of HGF in macular edema in ischemic retinopathies.

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“…Labs, Burlingame, CA, USA) was used for perfusion to label vascular ECs and to obtain the angiographic images as previously described 31 . Mice were anesthetized and their chests were opened to expose the heart; the right atrium was cut for drainage, a 27-gauge cannula was inserted into left ventricle, and then perfused over a span of 1 minute with Con A (0.5 mL at 625 μg/mL in PBS).…”

Section: Morphological Analyses: Retinal Vessel Integrity Fluoresceimentioning

confidence: 99%

Ursodeoxycholic Acid Attenuates the Retinal Vascular Abnormalities in Anti-PDGFR-β Antibody-Induced Pericyte Depletion Mouse Models

Shiraya

Araki

Ueta

et al. 2020

Sci Rep

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As a clinical manifestations of diabetic retinopathy (DR), pericytes (pcs) loss from the capillary walls is thought to be an initial pathological change responsible for the breakdown of the blood-retinal barrier (BRB). This study was performed to investigate the effects of ursodeoxycholic acid (UDCA) in pc depletion mice by injection of an antibody against platelet-derived growth factor reception-β (pDGfR-β clone APB5). To assess the integrity of the retinal vessels, their density, diameters, vessel branching points, and number of acellular capillaries were evaluated. While all types of retinal vessels became enlarged in APB5-induced mice, treatment with UDCA rescued the vasculature; the vessel density, diameter of the veins and capillaries, and vessel branching points were significantly lower in mice treated with UDCA. Although APB5-induced mice displayed progressive exacerbation of retinal edema, whole retinal thickness upon treatment with UDCA was significantly decreased. Additionally, UDCA reduced the expression of F4/80 + macrophages in the APB5-induced retina according to immunofluorescent labeling. UDCA also reduced the increased expression of angiogenic factors and inflammatory mediators (vascular endothelial growth factor, intercellular adhesion molecule-1, and monocyte chemotactic protein-1). These findings suggest that UDCA can be used to prevent the progression of and treat DR. Diabetes and its related complications, including retinopathy, have a great social and economic burden worldwide 1,2. The World Health Organization has suggested that diabetic retinopathy (DR) is responsible for 15-17% of total blindness cases in the United States and Europe 1,3-5. Pericytes (PC) not only provide mechanical support, but also maintain vessel wall integrity by interacting with endothelial cells (EC) via secretory signals and direct cell-to-cell contact 6. As an early clinical manifestation of DR, PC depletion from the capillary wall is considered an early pathological change that causes the blood-retinal barrier (BRB) to collapse and subsequent vascular hyperpermeability 7. Furthermore, PC depletion results in vascular abnormalities along with upregulation of angiogenic factors and inflammatory cytokines 8,9. In cases of more advanced DR, vascular occlusion induces retinal hypo-perfusion and hypoxia, resulting in abnormal angiogenesis that directly causes blindness due to vitreous hemorrhage and tractional retinal detachment 10. In recent years, intravitreal injections of anti-vascular endothelial growth factor (VEGF) agents have been effectively used to treat diabetic macular edema 11-13 and have also empirically indicated the involvement of the VEGF signaling and inflammation in BRB breakdown in DR 14. However, frequent injections are burdensome for patients and physicians, and are associated with a very high cost to the healthcare system. Preventative medicine of DR with a safe and low-burden treatment for patients that requires investigation. Ursodeoxycholic acid (UDCA), a product of the hydrolysis of taurour...

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Reversible retinal vessel closure from VEGF-induced leukocyte plugging

Cited by 45 publications

References 66 publications

Sustained treatment of retinal vascular diseases with self-aggregating sunitinib microparticles

Sustained treatment of retinal vascular diseases with self-aggregating sunitinib microparticles

Hepatocyte growth factor is upregulated in ischemic retina and contributes to retinal vascular leakage and neovascularization

Ursodeoxycholic Acid Attenuates the Retinal Vascular Abnormalities in Anti-PDGFR-β Antibody-Induced Pericyte Depletion Mouse Models

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