Circulation Research. 2004
Published online before print March 4, 2004, doi: 10.1161/01.RES.0000125295.43813.1F
Published online before print March 4, 2004, doi: 10.1161/01.RES.0000125295.43813.1F
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Submitted on August 14, 2003
Revised on February 20, 2004
Accepted on February 23, 2004
Age-Related Changes in Vascular Endothelial Growth Factor Dependency and Angiopoietin-1-Induced Plasticity of Adult Blood Vessels
Fabienne Baffert ;
From the Department of Anatomy (F.B., M.R.-D., T.L., D.M.M.), Cardiovascular Research Institute and Comprehensive Cancer Center, University of California, San Francisco, Calif; Regeneron Pharmaceuticals (G.T.), Tarrytown, NY; University of Texas (R.B.), Southwestern Medical Center, Dallas, Tex.
* To whom correspondence should be addressed. E-mail: dmcd{at}itsa.ucsf.edu.
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.
Key words: angiogenesis • angiopoietin-1 • microvasculature • vascular endothelial growth factor • vascular endothelial growth factor receptor-2
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