Age-related changes in vascular endothelial growth factor dependency and angiopoietin-1-induced plasticity of adult blood vessels.
Vascular endothelial growth factor (VEGF) and angiopoietin-1 (Ang1) are essential for vascular development, but this dependency has been assumed not to persist into adult life. In this study, we report that after 10 days of systemic treatment of 4-, 8-, and 16-week-old mice with VEGF-Trap, an inhibitor of VEGF, the number of capillaries in the tracheal mucosa was reduced by 39%, 28%, and 14%, respectively. The magnitude of the reduction decreased with age (r2=0.6, P<0.001), but was still significant at 16 weeks. A corresponding age-related decrease in vascular endothelial growth factor receptor-2 (VEGFR-2) immunoreactivity suggests that diminished VEGFR-2 expression may contribute to resistance to VEGF signaling inhibition. VEGF-Trap further reduced VEGFR-2 expression in tracheal capillaries. By comparison, systemic treatment with adenovirus encoding Ang1 led to a significant enlargement of tracheal venules with little age effect (64%, 56%, and 49% increase in diameter at 10 days). When Ang1 was given in combination with VEGF-Trap, tracheal vessels presented the typical response to each factor, showing that the Ang1 effect was not VEGF-mediated, yet Ang1 seems to have a protective effect, as judged by prevention of VEGF-Trap-induced reduction in tracheal capillaries in the oldest group. Together, these findings indicate that VEGF and Ang1 participate in blood vessel survival and plasticity in adult life.
Department of Anatomy, Cardiovascular Research Institute and Comprehensive Cancer Center, University of California, San Francisco, Calif, USA.
Fabienne
F
Baffert
Gavin
G
Thurston
Michael
M
Rochon-Duck
Tom
T
Le
Rolf
R
Brekken
Donald M
DM
McDonald
D000375:Aging / Q000378:metabolism; D000818:Animals; D002196:Capillaries / Q000187:drug effects / Q000648:ultrastructure; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D008297:Male; D051379:Mice; D009092:Mucous Membrane / Q000098:blood supply / Q000254:growth & development; D020286:Pericytes / Q000648:ultrastructure; D040262:Receptors, Vascular Endothelial Growth Factor; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D013047:Specific Pathogen-Free Organisms; D014132:Trachea / Q000098:blood supply* / Q000254:growth & development; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000096:biosynthesis / Q000235:genetics; D014699:Venules / Q000187:drug effects / Q000648:ultrastructure
C488617:Ad-Ang1 protein; D011993:Recombinant Fusion Proteins; C475927:VEGF-Trap fusion protein, recombinant; D042461:Vascular Endothelial Growth Factor A; D040262:Receptors, Vascular Endothelial Growth Factor; D040301:Vascular Endothelial Growth Factor Receptor-2