Abstract
Our previous data suggested that angiopoietin-2 (Ang-2) is linked to pericyte loss, thereby playing an important role in diabetic retinopathy. In this study, we investigated the effect of retinal overexpression of human Ang-2 (mOpsinhAng2 mouse) on vascular morphology in non-diabetic and streptozotozin-induced diabetic animals. Pericyte (PC) coverage and acellular capillary (AC) formation were quantitated in retinal digest preparations after 3 and 6 months of diabetes duration. The degree of retinopathy in non-diabetic mOpsinhAng2 mice at 3 months (−21% PC, +49% AC) was comparable to age-matched diabetic wild type mice. Diabetic mOpsinhAng2 mice exhibited significantly worse vascular pathology than wild type counterparts at 6 months. Quantitative PCR revealed that human Ang-2 mRNA was highly overexpressed in retinas of transgenic mice. Our data demonstrate that overexpression of Ang-2 in the retina enhances vascular pathology, indicating that Ang-2 plays an essential role in diabetic vasoregression via destabilization of pericytes.
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Chi JT, Chang HY, Haraldsen G et al (2003) Endothelial cell diversity revealed by global expression profiling. Proc Natl Acad Sci USA 100:10623–10628
Cogan DG, Toussaint D, Kuwabara T (1961) Retinal vascular patterns. IV. Diabetic retinopathy. Arch Ophthalmol 66:366–378
Enge M, Bjarnegard M, Gerhardt H et al (2002) Endothelium-specific platelet-derived growth factor-B ablation mimics diabetic retinopathy. EMBO J 21:4307–4316
Feng Y, vom Hagen F, Pfister F et al (2007) Impaired pericyte recruitment and abnormal retinal angiogenesis as a result of angiopoietin-2 overexpression. Thromb Haemost 97:99–108
Gale NW, Thurston G, Hackett SF et al (2002) Angiopoietin-2 is required for postnatal angiogenesis and lymphatic patterning, and only the latter role is rescued by Angiopoietin-1. Dev Cell 3:411–423
Hackett SF, Ozaki H, Strauss RW et al (2000) Angiopoietin 2 expression in the retina: upregulation during physiologic and pathologic neovascularization. J Cell Physiol 184:275–284
Hackett SF, Wiegand S, Yancopoulos G et al (2002) Angiopoietin-2 plays an important role in retinal angiogenesis. J Cell Physiol 192:182–187
Hammes HP, Lin J, Wagner P et al (2004) Angiopoietin-2 causes pericyte dropout in the normal retina: evidence for involvement in diabetic retinopathy. Diabetes 53:1104–1110
Maisonpierre PC, Suri C, Jones PF et al (1997) Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science 277:55–60
Matsumara T, Hammes HP, Thornalley P et al. (2000) Hyperglycemia increases angiopoietin-2 expression in retinal Muller cells through through superoxide-induced overproduction of a-oxoaldehyde age precursors (abstract). Diabetes 49: A55
Ochs M, Mayhew TM, Knabe W (2000) To what extent are the retinal capillaries ensheathed by Muller cells? A stereological study in the tree shrew Tupaia belangeri. J Anat 196(Pt 3):453–461
Ohashi H, Takagi H, Koyama S et al (2004) Alterations in expression of angiopoietins and the Tie-2 receptor in the retina of streptozotocin induced diabetic rats. Mol Vis 10:608–617
Orlidge A, D’Amore PA (1987) Inhibition of capillary endothelial cell growth by pericytes and smooth muscle cells. J Cell Biol 105:1455–1462
Pfister F, Feng Y, vom Hagen F et al (2008) Pericyte migration: a novel mechanism of pericyte loss in experimental diabetic retinopathy. Diabetes 57:2495–2502
Watanabe D, Suzuma K, Suzuma I et al (2005) Vitreous levels of angiopoietin 2 and vascular endothelial growth factor in patients with proliferative diabetic retinopathy. Am J Ophthalmol 139:476–481
Yao D, Taguchi T, Matsumura T et al (2006) Methylglyoxal modification of mSin3A links glycolysis to angiopoietin-2 transcription. Cell 124:275–286
Acknowledgments
This study was supported by grants from the DFG, the DDG and the GRK 880. The authors thank Petra Bugert, Nadine Dietrich and Valerie Schwarz for their grateful support.
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Pfister, F., Wang, Y., Schreiter, K. et al. Retinal overexpression of angiopoietin-2 mimics diabetic retinopathy and enhances vascular damages in hyperglycemia. Acta Diabetol 47, 59–64 (2010). https://doi.org/10.1007/s00592-009-0099-2
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DOI: https://doi.org/10.1007/s00592-009-0099-2