Pericyte migration: a novel mechanism of pericyte loss in experimental diabetic retinopathy.
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.


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.
5th Medical Department, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
Frederick
F
Pfister
Yuxi
Y
Feng
Franziska
F
vom Hagen
Sigrid
S
Hoffmann
Grietje
G
Molema
Jan-Luuk
JL
Hillebrands
Moshe
M
Shani
Urban
U
Deutsch
Hans-Peter
HP
Hammes
D042702:Angiopoietin-2 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002196:Capillaries / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement / Q000502:physiology*; D003930:Diabetic Retinopathy / Q000473:pathology* / Q000503:physiopathology; D004195:Disease Models, Animal; D006943:Hyperglycemia / Q000473:pathology* / Q000503:physiopathology; D007763:Lac Operon; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D020286:Pericytes / Q000378:metabolism / Q000473:pathology*; D042787:Receptor, TIE-2 / Q000378:metabolism
D042702:Angiopoietin-2; D042787:Receptor, TIE-2