Angiopoietin-2 deficiency decelerates age-dependent vascular changes in the mouse retina.
Retinae of aged humans show signs of vascular regression. Vascular regression involves a mismatch between Angiopoietin-2 (Ang-2) and vascular endothelial growth factor (VEGF) expression. We used heterozygous Ang-2 deficient (Ang2LacZ) mice to evaluate murine retinal vascular changes and gene expression of growth factors. Vascular changes were assessed by quantitative retinal morphometry and gene expression levels of growth factors were measured by quantitative PCR. The numbers of endothelial cells and pericytes did not change in the Ang2LacZ retinae with age, whereas they decreased throughout the age spectrum studied in the wild type retinae. Moreover, vascular regression significantly decelerated in the heterozygous Ang2LacZ retinae (200% to 1 month), while the formation of acellular capillaries was significantly increased at 13 months in the wild type retinae (340% to 1 month). Gene expression analysis revealed that VEGF, Ang-1, PDGF-B and Ang2 mRNA levels were decreased in the wild type retinae at 9 month of age. However, the decrease of Ang-2 was smaller compared with other genes. While VEGF levels dropped in wild type mice up to 60% compared to 1 month, VEGF increased in heterozygous Ang-2 deficient retinae at an age of 9 months (141% to 1 month). Similarly, Ang-1 levels decreased in wild type mice (45% to 1 month), but remained stable in Ang2LacZ mice. These data suggest that Ang-2 gene dose reduction decelerates vasoregression in the retina with age. This effect links to higher levels of survival factors such as VEGF and Ang-1, suggesting that the ratio of these factors is critical for capillary cell survival.
Feng
Yuxi
Y
5th Medical Clinic, Faculty of Clinical Medicine, University of Heidelberg, Mannheim, Germany.
Pfister
Frederick
F
Schreiter
Kay
K
Wang
Yumei
Y
Stock
Oliver
O
Vom Hagen
Franziska
F
Wolburg
Hartwig
H
Hoffmann
Sigrid
S
Deutsch
Urban
U
Hammes
Hans-Peter
HP
D000375:Aging / Q000502:physiology*; D042683:Angiopoietin-1 / Q000235:genetics / Q000378:metabolism; D042702:Angiopoietin-2 / Q000172:deficiency*; D000818:Animals; D002470:Cell Survival; D005786:Gene Expression Regulation; D051379:Mice; D020574:Proto-Oncogene Proteins c-sis / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012160:Retina / Q000473:pathology* / Q000648:ultrastructure; D012171:Retinal Vessels / Q000473:pathology* / Q000648:ultrastructure; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
D042683:Angiopoietin-1; D042702:Angiopoietin-2; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A