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.
Baffert
Fabienne
F
Department of Anatomy, Cardiovascular Research Institute and Comprehensive Cancer Center, University of California, San Francisco, Calif, USA.
Thurston
Gavin
G
Rochon-Duck
Michael
M
Le
Tom
T
Brekken
Rolf
R
McDonald
Donald M
DM
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