Biomedical subjects

Stanley A Vinores

Publications and source records attributed to Stanley A Vinores.

8 recordsLinked to original sources

PubMed2006

TNF-alpha is critical for ischemia-induced leukostasis, but not retinal neovascularization nor VEGF-induced leakage.

Vascular endothelial growth factor (VEGF) and tumor necrosis factor-alpha (TNF-alpha) show significant overlap with regard to their effects in the eye. It has been postulated that VEGF-induced leukostasis, breakdown of the blood-retinal barrier, and ischemia-induced retinal neovascularization may be mediated, at least in part, through TNF-alpha. In this study, we used mice deficient in TNF-alpha to test our hypothesis. Compared to wild type mice, TNF-alpha-deficient mice showed an 80% reduction in leukocyte accumulation in retinal vessels after intravitreous injection of VEGF, and 100% reductions after intravitreous injections of interleukin-1beta (IL-1beta) or platelet-activating factor (PAF). The increase in retinal vascular permeability induced by injection of PAF was significantly reduced in mice lacking TNF-alpha, but VEGF- and IL-1beta-induced leakage was unaffected. Compared to wild type mice with oxygen-induced ischemic retinopathy, TNF-alpha-deficient mice with ischemic retinopathy showed significantly reduced leukostasis and mild reduction in vascular leakage, but no significant difference in retinal neovascularization. These data suggest that TNF-alpha mediates VEGF-, IL-1beta-, and PAF-induced leukostasis and vascular leakage mediated by PAF, but not leakage caused by VEGF or IL-1beta. Ischemia-induced retinal neovascularization, which has previously been shown to require VEGF, does not require TNF-alpha and is unaffected by attenuation of leukostasis.

Animals↗

PubMed2006

Implication of the hypoxia response element of the Vegf promoter in mouse models of retinal and choroidal neovascularization, but not retinal vascular development.

Retinal neovascularization (NV) and macular edema, resulting from blood-retinal barrier (BRB) breakdown, are major causes of visual loss in ischemic retinopathies. Choroidal NV (CNV) occurs in diseases of the retinal pigmented epithelium/Bruch's membrane complex and is another extremely prevalent cause of visual loss. We used mice in which the hypoxia response element (HRE) is deleted from the vascular endothelial growth factor (vegf) promoter (Vegf(delta/delta) mice) to explore the role of induction of VEGF through the HRE in these disease processes. Compared to wild type (Vegf+/+) mice with oxygen-induced ischemic retinopathy (OIR) in which vegf mRNA levels were increased and prominent retinal NV and BRB breakdown occurred, Vegf(delta/delta) littermates with OIR failed to increase vegf mRNA levels in the retina and had significantly less retinal NV and BRB breakdown, but showed prominent dilation of some superficial retinal vessels. Vegf(+/delta) littermates with ischemic retinopathy developed comparable retinal NV to Vegf+/+ mice, exhibited intermediate levels of BRB breakdown, and did not show vasodilation. In a mouse model of CNV, due to laser-induced rupture of Bruch's membrane, the area of CNV at Bruch's membrane rupture sites was more than tenfold greater in Vegf+/+ mice than in Vegf(delta/delta) littermates. In contrast to these dramatic differences in pathologic ocular NV, Vegf(delta/delta) mice showed subtle differences in retinal vascular development compared to Vegf+/+ mice; it was slightly delayed, but otherwise normal. These data suggest that induction of VEGF through the HRE in its promoter is critical for retinal and CNV, but not for retinal vascular development.

Animals↗

PubMed2004

Mouse model of post-surgical breakdown of the blood-retinal barrier.

PURPOSE: Post-surgical macular edema is an important clinical problem resulting from breakdown of the blood-retinal barrier (BRB) after surgery. This study was designed to develop a mouse model of post-surgical BRB breakdown. METHODS: Two 25-gauge needles, one for infusion and one for aspiration, were inserted through the limbus and into the lens of one eye of adult male C57BL/6 mice. The anterior portion of the lens was aspirated and the fellow eye was untreated. At several time points after surgery, the integrity of the BRB was assessed quantitatively, using [3H]mannitol as a tracer, or qualitatively, using immunohistochemical staining for albumin. RESULTS: Eyes with partial lens extraction had a significant increase in retinal vascular leakage one day after surgery, which persisted two and three days after surgery, but by five days, was not significantly different from controls. Immunohistochemical staining for albumin demonstrated that the breech in the barrier was sufficient to allow passage of a 60kDa protein into the retina, and was localized predominantly to retinal vessels. CONCLUSIONS: Partial lens extraction in mice results in BRB breakdown (primarily the inner BRB) that is highly reproducible in the severity of leakage and its time course. This provides a valuable tool for investigation of the molecular pathogenesis and new treatment approaches for post-surgical breakdown of the BRB.

Animals↗

PubMed2003

Photoreceptor-specific overexpression of platelet-derived growth factor induces proliferation of endothelial cells, pericytes, and glial cells and aberrant vascular development: an ultrastructural and immunocytochemical study.

Platelet-derived growth factor (PDGF) is necessary for the normal development of the retinal vasculature and its overexpression is likely to contribute to proliferative retinal disorders, such as proliferative vitreoretinopathy. Transgenic mice that overexpress PDGF-B in the photoreceptors (rho/PDGF-B mice) develop traction retinal detachment. In the present study, a detailed histopathological analysis was performed in rho/PDGF-B mice. In these transgenic mice, endothelial cells, pericytes, and glial cells begin to proliferate at postnatal day 7 (P7). All three cell types increase in numbers, forming a highly vascularized cell mass, which reaches a maximum thickness at P14. Cords of endothelial cells and glia invade the retina and exert traction, generating retinal folds; however, the deep capillary bed never forms. Griffonia simplicifolia isolectin B4 (GSA)-positive endothelial cells form tubes and penetrate the retina to the level of the outer plexiform layer, but they never interconnect to form the deep capillary bed. The vessels within the cell mass are patent, but have a very immature morphology. They often are thin-walled with fenestrations. Pericytes and glial cells are usually found in clusters and are not associated with the abnormal vessels. The lack of this association may account for the failure to form a mature vasculature.

Actins↗

PubMed2003

Inhibition of protein kinase C decreases prostaglandin-induced breakdown of the blood-retinal barrier.

Breakdown of the blood-retinal barrier (BRB) occurs in several retinal diseases and is a major cause of visual loss. Vascular endothelial growth factor (VEGF) has been implicated as a cause of BRB breakdown in diabetic retinopathy and other ischemic retinopathies, and there is evidence to suggest that other vasopermeability factors may act indirectly through VEGF. In this study, we investigated the effect of several receptor kinase inhibitors on BRB breakdown resulting from VEGF, tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), insulin-like growth factor-1 (IGF-1), prostaglandin E1 (PGE(1)), or PGE(2). Inhibitors of VEGF receptor kinase, including PKC412, PTK787, and SU1498, decreased VEGF-induced breakdown of the BRB. None of the inhibitors blocked leakage caused by TNF-alpha, IL-1beta, or IGF-1 and only PKC412, an inhibitor of protein kinase C (PKC) as well as VEGF and platelet-derived growth factor (PDGF) receptor kinases, decreased leakage caused by prostaglandins. Since the other inhibitors of VEGF and/or PDGF receptor kinases that do not also inhibit PKC had no effect on prostaglandin-induced breakdown of the BRB, these data implicate PKC in retinal vascular leakage caused by prostaglandins. PKC412 may be useful for treatment of post-operative and inflammatory macular edema, in which prostaglandins play a role, as well as macular edema associated with ischemic retinopathies.

Alprostadil↗

PubMed2003

Technology evaluation: pegaptanib, Eyetech/Pfizer.

Eyetech Pharmaceuticals and Pfizer are co-developing the anti-vascular endothelial growth factor aptamer, pegaptanib, as an angiogenesis inhibitor for the potential treatment of age-related macular degeneration and diabetic macular edema, in addition to other ocular diseases. Gilead was previously investigating the aptamer for the potential treatment of cancer, however, no data have been published for this indication since 1999.

Angiogenesis Inhibitors↗

PubMed2002

Laser targeted photo-occlusion of rat choroidal neovascularization without collateral damage.

Laser targeted photo-occlusion (LTO) is a novel method being developed to treat choroidal neovascular membranes (CNV) in age-related and other macular degenerations. A photosensitive agent, encapsulated in heat-sensitive liposomes, is administered intravenously. A low power laser warms the targeted tissue and releases a bolus of photosensitizer. The photosensitizer is activated after it clears from the normal choriocapillaris but not from the CNV. Forty-five experimental CNV were induced in seven rats. Five weeks after LTO, complete occlusion was observed by laser targeted angiography (LTA) in 76% of treated CNV, and partial occlusion was found in the remaining 24%. The tissues outside the CNV but within the area treated by LTO showed no flow alteration and no dye leakage. All untreated CNV were patent on LTA at 5 weeks. Light microscopy and electron microscopy confirmed the results in treated and control lesions. Moreover, treated areas next to lesions showed normal photoreceptors, retinal pigment epithelium (RPE), Bruch's membrane and choriocapillaris. These results indicate that LTO may improve current photodynamic therapy by alleviating the need for repeated treatments and by avoiding the long-term risks associated with damage to the RPE and occlusion of normal choriocapillaries.

Animals↗

PubMed2002

Quantitative assessment of the integrity of the blood-retinal barrier in mice.

PURPOSE: The purpose of this study was to develop and characterize a quantitative assay of blood-retinal barrier (BRB) function in mice and to determine the effect of several purported vasopermeability factors on the BRB. METHODS: Adult C57BL/6J mice were treated with three regimens of increasingly extensive retinal cryopexy and subsequently were given an intraperitoneal injection of 1 microCi/g body weight of [(3)H]mannitol. At several time points, the amount of radioactivity per milligram tissue was compared in retina, lung, and kidney. Time points that maximize signal-to-background differential in the retina were identified, and the ratio of counts per minute (CPM) per milligram retina to CPM per milligram lung (retina-to-lung leakage ratio, RLLR) or kidney (retina-to-renal leakage ratio, RRLR) were calculated. This technique was then used to compare the amount of BRB breakdown that occurs after intravitreous injection of vascular endothelial growth factor (VEGF), insulin-like growth factor (IGF)-1, prostaglandin (PG) E(1), PGE(2), interleukin (IL)-1beta, or tumor necrosis factor (TNF)-alpha. RESULTS: Twenty-four hours after retinal cryopexy, there was a higher level of radioactivity in treated than in control retinas, and the signal-to-background difference was optimal when measurements were obtained 1 hour after injection of [(3)H]mannitol. In untreated mice, the RLLR was 0.30 +/- 0.02 and the RRLR was 0.22 +/- 0.01. Twenty-four hours after one 5-second application of retinal cryopexy, the RLLR was 0.73 +/- 0.20 and the RRLR was 0.71 +/- 0.23. With increasing amounts of cryopexy, there was an increase in the RLLR and RRLR, so that after two 10-second applications, the RLLR was 1.66 +/- 0.31 and the RRLR was 1.47 +/- 0.20. Intravitreous injection of VEGF, IGF-1, PGE(1), PGE(2), IL-1beta, or TNF-alpha each caused significant increases in the RLLR and RRLR, but there were some differences in potency and time course. VEGF caused prominent BRB breakdown at 6 hours that returned to near normal by 24 hours. IL-1beta also caused relatively rapid breakdown of the BRB, but its effect was more prolonged than that caused by VEGF. There was delayed, but substantial breakdown of the BRB after injection of TNF-alpha. IGF-1, PGE(2), and PGE(1) caused less severe, relatively delayed, and more prolonged BRB breakdown. CONCLUSIONS: Measurement of the RLLR or RRLR after intraperitoneal injection of [(3)H]mannitol in mice provides a quantitative assessment of BRB function that is normalized and can therefore be compared from assay to assay. Comparison of the extent and duration of BRB breakdown after intravitreous injection of vasoactive substances shows that agents can be grouped by resultant extent and time course of leakage. Additional studies are needed to determine whether this grouping has its basis in shared mechanisms of BRB disruption.

Animals↗