Retinal Vascular Patterns

Cogan, David G.; Toussaint, D; Kuwabara, Toichiro

doi:10.1001/archopht.1961.00960010368014

Cited by 674 publications

(136 citation statements)

References 19 publications

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“…This finding may also be important as retinal pericytes are characteristically lost early in the course of diabetic retinopathy (75,95). Thus, even with diminishing numbers, significant localized VEGF expression may be present.…”

Section: Fig 12mentioning

confidence: 97%

Stretch-induced Retinal Vascular Endothelial Growth Factor Expression Is Mediated by Phosphatidylinositol 3-Kinase and Protein Kinase C (PKC)-ζ but Not by Stretch-induced ERK1/2, Akt, Ras, or Classical/Novel PKC Pathways

Suzuma¹,

Suzuma²,

Ueki³

et al. 2002

Journal of Biological Chemistry

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Stretch-induced expression of vascular endothelial growth factor (VEGF) is thought to be important in mediating the exacerbation of diabetic retinopathy by systemic hypertension. However, the mechanisms underlying stretch-induced VEGF expression are not fully understood. We present novel findings demonstrating that stretch-induced VEGF expression in retinal capillary pericytes is mediated by phosphatidylinositol (PI) 3-kinase and protein kinase C (PKC)-but is not mediated by ERK1/2, classical/novel isoforms of PKC, Akt, or Ras despite their activation by stretch. Cardiac profile cyclic stretch at 60 cpm increased VEGF mRNA expression in a time-and magnitude-dependent manner without altering mRNA stability. Stretch increased ERK1/2 phosphorylation, PI 3-kinase activity, Akt phosphorylation, and PKCactivity. Signaling pathways were explored using inhibitors of PKC, MEK1/2, and PI 3-kinase; adenovirus-mediated overexpression of ERK, PKC-␣, PKC-␦, PKC-, and Akt; and dominant negative (DN) mutants of ERK, PKC-, Ras, PI 3-kinase and Akt. Although stretch activated ERK1/2 through a Ras-and PKC classical/novel isoformdependent pathway, these pathways were not responsible for stretch-induced VEGF expression. Overexpression of DN ERK and Ras had no effect on VEGF expression in these cells. In contrast, DN PI 3-kinase as well as pharmacologic inhibitors of PI 3-kinase blocked stretch-induced VEGF expression. Although stretch-induced PI 3-kinase activation increased both Akt phosphorylation and activity of PKC-, VEGF expression was dependent on PKCbut not Akt. In addition, PKC-did not mediate stretchinduced ERK1/2 activation. These results suggest that stretch-induced expression of VEGF involves a novel mechanism dependent upon PI 3-kinase-mediated activation of PKC-that is independent of stretch-induced activation of ERK1/2, classical/novel PKC isoforms, Ras, or Akt. This mechanism may play a role in the well documented association of concomitant hypertension with clinical exacerbation of neovascularization and vascular permeability.One in four American adults has hypertension, while 5.9% of the United States population (over 15 million people) have diabetes. Diabetic retinopathy is the leading cause of new onset blindness in the United States among working age individuals (1) and is exacerbated by coexistent systemic hypertension (2-4). Sight-threatening diabetic retinopathy is characterized by development of retinal neovascularization and/or retinal vascular permeability (5). Hypertension increases the risk of retinopathy progression, development of neovascularization (2, 6, 7), and retinal vascular permeability (8, 9) by up to 3-fold. Blood pressure control reduces both retinopathy progression and severe visual loss (10). Even in normotensive diabetic patients retinopathy is associated with higher systolic blood pressure (11). Other vision-threatening conditions such as hypertensive retinopathy (12) and age-related macular degeneration are also aggravated by hypertension (13).Although the mechanisms underlying the exace...

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Section: Fig 12mentioning

confidence: 97%

Stretch-induced Retinal Vascular Endothelial Growth Factor Expression Is Mediated by Phosphatidylinositol 3-Kinase and Protein Kinase C (PKC)-ζ but Not by Stretch-induced ERK1/2, Akt, Ras, or Classical/Novel PKC Pathways

Suzuma¹,

Suzuma²,

Ueki³

et al. 2002

Journal of Biological Chemistry

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“…Endothelial cells have been implicated in the pathogenesis of diabetic complications in the development of both micro-and macroangiopathy (1)(2)(3). Studies of cells in culture have demonstrated differences in the growth requirements for endothelium and other vascular cells of large vessels and capillaries, although detailed characterization of these differences has not been established (4)(5)(6)(7).…”

Section: Introductionmentioning

confidence: 99%

Differential responsiveness to insulin of endothelial and support cells from micro- and macrovessels.

King¹,

Buzney²,

Kahn³

et al. 1983

J. Clin. Invest.

223

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A B S T R A C T The pathologies of diabetic micro-and macroangiopathy are different, suggesting that diabetes affects these two types of vascular tissue in a dissimilar manner. We have compared insulin receptors and the effects of insulin on cultured endothelium from calf retinal capillaries and aorta, and the vascular supporting cells, retinal pericytes, and aortic smooth muscle cells. '251-insulin binds to high affinity insulin receptors on all four cell types. Receptor concentrations were similar except for aortic smooth muscle cells, which have 10-fold fewer receptors than the other cell types. Insulin at a concentration of 10 ng/ ml stimulated ['4C]glucose incorporation into glycogen in retinal endothelial cells and pericytes and aortic smooth muscle cells, but had no effect on aortic endothelium. Insulin over a concentration range of 10 ng/ml-10 ,ug/ml, stimulated [3H]thymidine incorporation into the DNA of retinal pericytes, and endothelial cells and aortic smooth muscle cells but had no effect on aortic endothelial cells. These data suggested that a differential response to insulin may exist between endothelium of micro-and macrovasculature, and suggest that retinal capillary endothelium and retinal pericytes are both very insulin-sensitive tissues.

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“…The precise interactions between these molecules in causing apoptosis and the importance of oxidant stress as a contributory factor remain to be determined. Diabetes 54:1838 -1845, 2005 P ericyte (PC) drop out due to apoptosis has long been considered an early event in diabetic retinopathy (1). Theories to explain why it occurs have predominantly focused on hyperglycemia.…”

mentioning

confidence: 99%

Palmitate-Induced Apoptosis in Cultured Bovine Retinal Pericytes

et al. 2005

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Apoptosis of pericytes (PCs) is an early event in diabetic retinopathy. It is generally thought to be a consequence of sustained hyperglycemia. In keeping with this, long-term (>7 days) incubation of cultured PCs in a high-glucose media has been shown to increase apoptosis. We examine here whether the saturated free fatty acid palmitate, the concentration of which is often elevated in diabetes, has similar effects on cultured PCs. Incubation with 0.4 mmol/l palmitate for 24 h induced both oxidant stress and apoptosis, as evidenced by a sixfold increase in DCF fluorescence and a twofold increase in caspase-3 activation, respectively. NAD(P)H oxidase appeared to be involved in these responses, since overexpression of dominant-negative subunits of NAD(P)H oxidase, such as phox47(DN), diminished oxidant stress, and phox67(DN) and N-17 RAC1(DN) prevented the increase in caspase-3 activity. Likewise, overexpression of vRAC, a constitutively active RAC1, increased caspase-3 activity to the same extent as palmitate alone. The effects of vRAC and palmitate were not additive. In parallel with the increases in oxidative stress, the redox-sensitive transcription factor nuclear factor-B (NF-B) was activated in cells incubated with 0.4 mmol/l palmitate. Furthermore, inhibition of NF-B activation by various means inhibited caspase-3 activation. Finally, incubation with palmitate increased the cellular content of ceramide, a molecule linked to apoptosis and increases in oxidative stress and NF-B activation in other cells. In keeping with such a role, in PCs both coincubation with fumonisin B1 (a ceramide synthase inhibitor) and overexpression of ceramidase I reversed the proapoptotic effect of palmitate. On the other hand, they increased rather than decreased DCF fluorescence. In conclusion, the results suggest that palmitate-induced apoptosis in PCs is associated with activation of NAD(P)H oxidase and NF-B and an increase in ceramide. The precise interactions between these molecules in causing apoptosis and the importance of oxidant stress as a contributory factor remain to be determined.

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Retinal Vascular Patterns

Cited by 674 publications

References 19 publications

Stretch-induced Retinal Vascular Endothelial Growth Factor Expression Is Mediated by Phosphatidylinositol 3-Kinase and Protein Kinase C (PKC)-ζ but Not by Stretch-induced ERK1/2, Akt, Ras, or Classical/Novel PKC Pathways

Stretch-induced Retinal Vascular Endothelial Growth Factor Expression Is Mediated by Phosphatidylinositol 3-Kinase and Protein Kinase C (PKC)-ζ but Not by Stretch-induced ERK1/2, Akt, Ras, or Classical/Novel PKC Pathways

Differential responsiveness to insulin of endothelial and support cells from micro- and macrovessels.

Palmitate-Induced Apoptosis in Cultured Bovine Retinal Pericytes

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