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Published online June 16, 2008
Diabetes 57:2495-2502, 2008
DOI: 10.2337/db08-0325
© 2008 by the American Diabetes Association
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Pericyte Migration

A Novel Mechanism of Pericyte Loss in Experimental Diabetic Retinopathy

Frederick Pfister1, Yuxi Feng1, Franziska vom Hagen1,3, Sigrid Hoffmann2, Grietje Molema3, Jan-Luuk Hillebrands4, Moshe Shani5, Urban Deutsch6, and Hans-Peter Hammes1

1 5th Medical Department, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
2 Medical Research Center, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
3 Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
4 Department of Cell Biology, Section Immunology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
5 Institute of Animal Science, The Volcani Center, Bet Dagan, Israel
6 Theodor Kocher Institute of Berne, Berne, Switzerland

Corresponding author: Hans-Peter Hammes, hans-peter.hammes{at}med5.ma.uni-heidelberg.de

OBJECTIVE— The mechanism underlying pericyte loss during incipient diabetic retinopathy remains controversial. Hyperglycemia induces angiopoietin-2 (Ang-2) transcription, which modulates capillary pericyte coverage. In this study, we assessed loss of pericyte subgroups and the contribution of Ang-2 to pericyte migration.

RESEARCH DESIGN AND METHODS— Numbers of total pericytes and their subgroups were quantified in retinal digest preparations of spontaneous diabetic XLacZ mice. Pericytes were divided into subgroups according to their localization, their position relative to adjacent endothelial cells, and the expression of LacZ. The contribution of Ang-2 to pericyte migration was assessed in Ang-2 overexpressing (mOpsinhAng2) and deficient (Ang2LacZ) mice.

RESULTS— Pericyte numbers were reduced by 16% (P < 0.01) in XLacZ mice after 6 months of diabetes. Reduction of pericytes was restricted to pericytes on straight capillaries (relative reduction 27%, P < 0.05) and was predominantly observed in LacZ-positive pericytes (–20%, P < 0.01). Hyperglycemia increased the numbers of migrating pericytes (69%; P < 0.05), of which the relative increase due to diabetes was exclusively in LacZ-negative pericytes, indicating reduced adherence to the capillaries (176%; P < 0.01). Overexpression of Ang-2 in nondiabetic retinas mimicked diabetic pericyte migration of wild-type animals (78%; P < 0.01). Ang-2 deficient mice completely lacked hyperglycemia-induced increase in pericyte migration compared with wild-type littermates.

CONCLUSIONS— Diabetic pericyte loss is the result of pericyte migration, and this process is modulated by the Ang-Tie system.


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