Retinal vascular permeability suppression by topical application of a novel VEGFR2/Src kinase inhibitor in mice and rabbits.

Retinal and choroidal vascular diseases, with their associated abnormalities in vascular permeability, account for the majority of patients with vision loss in industrialized nations. VEGF is upregulated in ischemic retinopathies such as diabetes and is known to dramatically alter vascular permeability in a number of nonocular tissues via Src kinase-regulated signaling pathways. VEGF antagonists are currently in clinical use for treating the new blood vessels and retinal edema associated with neovascular eye diseases, but such therapies require repeated intraocular injections. We have found that vascular leakage following intravitreal administration of VEGF in mice was abolished by systemic or topical delivery of what we believe is a novel VEGFR2/Src kinase inhibitor; this was confirmed in rabbits. The relevance of Src inhibition to VEGF-associated alterations in vascular permeability was further substantiated by genetic studies in which VEGF injection or laser-induced vascular permeability failed to augment retinal vascular permeability in Src-/- and Yes-/- mice (Src and Yes are ubiquitously expressed Src kinase family members; Src-/- and Yes-/- mice lacking expression of these kinases show no vascular leak in response to VEGF). These findings establish a role for Src kinase in VEGF-mediated retinal vascular permeability and establish a potentially safe and painless topically applied therapeutic option for treating vision loss due to neovascular-associated retinal edema.

Retinal angiogenesis in development and disease.

The retina has long been regarded as 'an approachable part of the brain' for investigating neurosensory processes. Cell biologists are now capitalizing on the accessibility of the retina to investigate important aspects of developmental angiogenesis, including how it relates to neuronal and glial development, morphogenesis, oxygen sensing and progenitor cells. Pathological angiogenesis also occurs in the retina and is a major feature of leading blinding diseases, particularly diabetic retinopathy. The retina and its clinical disorders have a pivotal role in angiogenesis research and provide model systems in which to investigate neurovascular relationships and angiogenic diseases.

Selective retinal therapy with microsecond exposures using a continuous line scanning laser.

PURPOSE: To evaluate the safety, selectivity, and healing of retinal lesions created using a continuous line scanning laser. METHODS: A 532-nm Nd:YAG laser (PASCAL) with retinal beam diameters of 40 µm and 66 µm was applied to 60 eyes of 30 Dutch-belted rabbits. Retinal exposure duration varied from 15 µs to 60 µs. Lesions were acutely assessed by ophthalmoscopy and fluorescein angiography. Retinal pigment epithelial (RPE) flatmounts were evaluated with live-dead fluorescent assay. Histological analysis was performed at 7 time points from 1 hour to 2 months. RESULTS: The ratios of the threshold of rupture and of ophthalmoscopic visibility to fluorescein angiography visibility (measures of safety and selectivity) increased with decreasing duration and beam diameter. Fluorescein angiography and live-dead fluorescent assay yielded similar thresholds of RPE damage. Above the ophthalmoscopic visibility threshold, histology showed focal RPE damage and photoreceptor loss at 1 day, without inner retinal effects. By 1 week, photoreceptor and RPE continuity was restored. By 1 month, photoreceptors appeared normal. CONCLUSION: : Retinal therapy with a fast scanning continuous laser achieves selective targeting of the RPE and, at higher power, of the photoreceptors without permanent scarring or inner retinal damage. Continuous scanning laser can treat large retinal areas within standard eye fixation time.

Expression of angiogenesis-related genes during retinal development.

We assessed expression patterns of angiogenesis-related genes in mouse retina during perinatal vascularization and in adulthood. Vascular endothelial growth factor (vegf) and its receptors flk, flt1, and neuropilins 1 and 2 are expressed in both vascularized and avascular areas. Within the expression domain for vegf, appearance of these receptors is spatially and temporally non-overlapping. Expression of flk, flt1, the matrix metalloproteinase mt1-mmp, and the tissue inhibitor of metalloproteinase timp2, but not of mmp2, mmp9, timp1, or timp3, correlates with inner retinal vascularization. In particular, expression of flk, flt1 and mt1-mmp in the inner retina begins adjacent to the optic nerve head and extends anteriorly during the first week of life, roughly concordant with the growth of retinal vessels. Several genes (vegf, flk, flt1, timp2, possibly mmp9) appear to be expressed by retinal glia.

Cellular mechanisms in retinal vascular development.

Since the pioneering work of Ashton and others, the primate retina has been thought to vascularize by a vasculogenic linkage of endothelial precursor cells. Recent investigations using specific histologic and morphologic criteria question the contribution of vasculogenesis to retinal development. Instead, in primates and mice cells previously designated as retinal angioblasts have been identified as astrocytes that form a vascular-like plexus preceding vessel invasion. Further, in primates and mice retinal vascularization proceeds via angiogenic sprouting from pre-existing vessels in all regions and stages. However, the developing retinal vasculature may utilize novel sources of endothelial cells, such as recruitment of circulating stem cells and redeployment of mural cells from regressing vessel segments. These results provide a framework for study of retinal vascular development, validate the common use of perinatal retinal models in angiogenesis research, and clarify the cellular basis of retinopathy of prematurity.

Diabetic retinopathy: a growing concern in an aging population.

Diabetic retinopathy--already the leading cause of irreversible blindness in working age Americans--is a rising threat as the diabetic population increases. Vision loss occurs due to retinal ischemia, retinal vascular exudation, intraocular hemorrhage, and ultimately, fibrotic complications. Optimal management of blood glucose levels and hypertension reduces the incidence and progression of retinopathy. Appropriate screening ensures early detection and management of diabetic retinopathy and reduces vision loss. Recent advances in our understanding of diabetic microvascular complications have led to new treatments that, along with refinements in laser and surgical techniques, are improving visual outcomes.

Current trends in age-related macular degeneration.

Age-related macular degeneration is the leading cause of irreversible blindness in older persons of the developed world. Addressing treatable risk factors reduces the incidence and progression of this condition. Recent advances in understanding and treating macular degeneration have dramatically improved the visual prognosis.

Visual loss associated with accidental subretinal injection of triamcinolone acetonide.

PURPOSE: To describe a complication of and possible retinal toxicity associated with sub-Tenon space injection of triamcinolone acetonide (TA). METHODS: An interventional case report is presented. During attempted sub-Tenon space injection of TA suspension (40 mg/mL), ≈0.3 mL was inadvertently injected into the temporal subretinal space. Potential sequelae of subretinal TA were assessed with fundus photography and visual field testing. RESULTS: Although subretinal TA resorbed quickly, a dense nasal visual field defect and retinal pigment epithelial changes corresponding to the area of initial subretinal TA deposition persisted for at least 18 months. CONCLUSION: Subretinal TA may exert retinal and retinal pigment epithelial toxicity.

Healing of retinal photocoagulation lesions.

PURPOSE: To systematically assess the changes in retinal morphology during the healing of retinal photocoagulation lesions of various clinical grades. METHODS: Rabbits were irradiated with a 532-nm Nd:YAG laser with a beam diameter of 330 microm at the retinal surface, a power of 175 mW, and pulse durations between 5 and 100 ms. Retinal lesions were clinically graded 1 minute after placement as invisible, barely visible, light, moderate, intense, very intense, and rupture and were assessed histologically at six time points from 1 hour to 4 months. RESULTS: At all pulse durations, the width of the retinal lesions decreased over time. At clinical grades of light and more severe (pulse durations, 10-100 ms), retinal scarring stabilized at 1 month at approximately 35% of the initial lesion diameter. Lesions clinically categorized as barely visible and invisible (pulse durations of 7 and 5 ms) exhibited coagulation of the photoreceptor layer but did not result in permanent scarring. In these lesions, photoreceptors completely filled in the damaged areas by 4 months. CONCLUSIONS: The decreasing width of the retinal damage zone suggests that photoreceptors migrating from unaffected areas fill in the gap in the photoreceptor layer. Laser photocoagulation parameters can be specified to avoid not only the inner retinal damage, but also permanent disorganization and scarring in the photoreceptor layer. These data may facilitate studies to determine those aspects of laser treatment necessary for beneficial clinical response and those that result in extraneous retinal damage.

Evaluation and management of suspected retinal detachment.

Retinal detachment often is a preventable cause of vision loss. There are three types of retinal detachments: exudative, tractional, and rhegmatogenous. The most common type is rhegmatogenous, which results from retinal breaks caused by vitreoretinal traction. Risk factors for retinal detachment include advancing age, previous cataract surgery, myopia, and trauma. Patients typically will present with symptoms such as light flashes, floaters, peripheral visual field loss, and blurred vision. Early intervention facilitates prevention of retinal detachment after formation of retinal breaks and improves visual outcomes of retinal detachment surgery. Patients with acute onset of flashes or floaters should be referred to an ophthalmologist.