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Diabetic retinopathy: targeting vasoregression.

Hammes HP, Feng Y, Pfister F, Brownlee M - Diabetes (2011)

View Article: PubMed Central - PubMed

Affiliation: University of Heidelberg, Mannheim, Germany. hans-peter.hammes@med5.ma.uni-heidelberg.de

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Diabetic retinopathy is characterized by gradually progressive alterations in the retinal microvasculature, leading to areas of retinal nonperfusion, increased vasopermeability, and in response to retinal nonperfusion, pathologic intraocular proliferation of retinal vessels... In contrast to many other vascular diseases, diabetic retinopathy in general has not been found to be strongly and unequivocally linked to genetic defects or polymorphisms... Among the few significantly associated genes are aldose reductase, the receptor for advanced glycation end products (RAGE), the integrin α2β1, and VEGF... Hyperglycemia-induced formation of methylglyoxal modifies mSin3A resulting in increased recruitment of O-GlcNAc transferase to an mSin3A-Sp3 complex and a subsequent increased modification of Sp3 by O-linked N-acetylglucosamine... Gluc-NAc modification of Sp3 causes decreased binding of the repressor complex to the glucose-responsive GC box in the Ang-2 promoter resulting in increased Ang-2 expression (Fig. 4)... The investigators categorized pericytes into three classes: 1) located at vessel branches (saddle pericytes), 2) located on straight parts of capillaries, and 3) showing different degrees of detachment from adjacent endothelial cells (migrating pericytes) (Fig. 5)... The investigators found that saddle pericytes remained unaffected by diabetes while only pericytes on straight parts of capillaries were reduced in diabetic retinae in parallel with an increased number of migrating pericytes... Together, these data favor pericyte migration as an important mechanism for diabetic pericyte loss... As noted in the traumatic brain injury model, stress-induced migration of pericytes resulted in their survival... Pericytes that stayed at their vessel location and did not migrate were prone to apoptosis, suggesting that migration of pericytes away from the capillary enables the pericyte to respond to trophic signaling molecules in the perivascular compartment... Erythropoietin (Epo) is another ischemia-induced growth factor that was recently identified as being important in the pathogenesis of proliferative diabetic retinopathy... The effect of Epo is mediated by a complex consisting of the Epo receptor, which is expressed throughout the entire retina, and the common chain receptor, which is expressed only in the vicinity of the superficial vascular layer, i.e., in the layer in which most neovascularizations develop... Low-dose Epo, which does not induce erythropoiesis over a period of up to 6 months, inhibited oxidative stress in the retinae of STZ-diabetic rats and reduced VEGF and Ang-2 levels... In the diabetic retina, elongase and desaturase profiles are substantially altered leading to a decrease in these ω-3 unsaturated fatty acids... As they can affect retinal gene expression with subsequent changes in cell differentiation and survival, diabetes-induced reductions in ω-3 PUFAs and increases in arachidonic acid can contribute to both vasoregression and neovascularization because of the lack in antiproliferative and proinflammatory effects.

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Phenotype of vasoregression in the diabetic retina. In both experimental diabetic rats and diabetic humans, capillary occlusions occur. Nondiabetic (A) and 6-month diabetic rat retina with acellular capillaries (arrows) (B). Nondiabetic (C) and diabetic (D) human retinal digest preparation. Periodic acid-Schiff staining (original magnification ×250).
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Figure 1: Phenotype of vasoregression in the diabetic retina. In both experimental diabetic rats and diabetic humans, capillary occlusions occur. Nondiabetic (A) and 6-month diabetic rat retina with acellular capillaries (arrows) (B). Nondiabetic (C) and diabetic (D) human retinal digest preparation. Periodic acid-Schiff staining (original magnification ×250).

Mentions: Most diabetes researchers and clinicians are aware of the major advances made in understanding the pathobiology of proliferative diabetic retinopathy. However mechanisms underlying the progressive alterations in retinal microvessels, which precede and stimulate neovascularization, are less well-known. In this review, current information about the pathogenesis of the primary lesion of diabetic retinopathy, retinal capillary vasoregression (see Fig. 1), is presented.


Diabetic retinopathy: targeting vasoregression.

Hammes HP, Feng Y, Pfister F, Brownlee M - Diabetes (2011)

Phenotype of vasoregression in the diabetic retina. In both experimental diabetic rats and diabetic humans, capillary occlusions occur. Nondiabetic (A) and 6-month diabetic rat retina with acellular capillaries (arrows) (B). Nondiabetic (C) and diabetic (D) human retinal digest preparation. Periodic acid-Schiff staining (original magnification ×250).
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3012202&req=5

Figure 1: Phenotype of vasoregression in the diabetic retina. In both experimental diabetic rats and diabetic humans, capillary occlusions occur. Nondiabetic (A) and 6-month diabetic rat retina with acellular capillaries (arrows) (B). Nondiabetic (C) and diabetic (D) human retinal digest preparation. Periodic acid-Schiff staining (original magnification ×250).
Mentions: Most diabetes researchers and clinicians are aware of the major advances made in understanding the pathobiology of proliferative diabetic retinopathy. However mechanisms underlying the progressive alterations in retinal microvessels, which precede and stimulate neovascularization, are less well-known. In this review, current information about the pathogenesis of the primary lesion of diabetic retinopathy, retinal capillary vasoregression (see Fig. 1), is presented.

View Article: PubMed Central - PubMed

Affiliation: University of Heidelberg, Mannheim, Germany. hans-peter.hammes@med5.ma.uni-heidelberg.de

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

Diabetic retinopathy is characterized by gradually progressive alterations in the retinal microvasculature, leading to areas of retinal nonperfusion, increased vasopermeability, and in response to retinal nonperfusion, pathologic intraocular proliferation of retinal vessels... In contrast to many other vascular diseases, diabetic retinopathy in general has not been found to be strongly and unequivocally linked to genetic defects or polymorphisms... Among the few significantly associated genes are aldose reductase, the receptor for advanced glycation end products (RAGE), the integrin α2β1, and VEGF... Hyperglycemia-induced formation of methylglyoxal modifies mSin3A resulting in increased recruitment of O-GlcNAc transferase to an mSin3A-Sp3 complex and a subsequent increased modification of Sp3 by O-linked N-acetylglucosamine... Gluc-NAc modification of Sp3 causes decreased binding of the repressor complex to the glucose-responsive GC box in the Ang-2 promoter resulting in increased Ang-2 expression (Fig. 4)... The investigators categorized pericytes into three classes: 1) located at vessel branches (saddle pericytes), 2) located on straight parts of capillaries, and 3) showing different degrees of detachment from adjacent endothelial cells (migrating pericytes) (Fig. 5)... The investigators found that saddle pericytes remained unaffected by diabetes while only pericytes on straight parts of capillaries were reduced in diabetic retinae in parallel with an increased number of migrating pericytes... Together, these data favor pericyte migration as an important mechanism for diabetic pericyte loss... As noted in the traumatic brain injury model, stress-induced migration of pericytes resulted in their survival... Pericytes that stayed at their vessel location and did not migrate were prone to apoptosis, suggesting that migration of pericytes away from the capillary enables the pericyte to respond to trophic signaling molecules in the perivascular compartment... Erythropoietin (Epo) is another ischemia-induced growth factor that was recently identified as being important in the pathogenesis of proliferative diabetic retinopathy... The effect of Epo is mediated by a complex consisting of the Epo receptor, which is expressed throughout the entire retina, and the common chain receptor, which is expressed only in the vicinity of the superficial vascular layer, i.e., in the layer in which most neovascularizations develop... Low-dose Epo, which does not induce erythropoiesis over a period of up to 6 months, inhibited oxidative stress in the retinae of STZ-diabetic rats and reduced VEGF and Ang-2 levels... In the diabetic retina, elongase and desaturase profiles are substantially altered leading to a decrease in these ω-3 unsaturated fatty acids... As they can affect retinal gene expression with subsequent changes in cell differentiation and survival, diabetes-induced reductions in ω-3 PUFAs and increases in arachidonic acid can contribute to both vasoregression and neovascularization because of the lack in antiproliferative and proinflammatory effects.

Show MeSH
Related in: MedlinePlus