VEGF blockade inhibits lymphocyte recruitment and ameliorates immune-mediated vascular remodeling.
BACKGROUND
There are conflicting data on the effects of vascular endothelial growth factor (VEGF) in vascular remodeling. Furthermore, there are species-specific differences in leukocyte and vascular cell biology and little is known about the role of VEGF in remodeling of human arteries.


OBJECTIVE
We sought to address the role of VEGF blockade on remodeling of human arteries in vivo.


RESULTS
We used an anti-VEGF antibody, bevacizumab, to study the effect of VEGF blockade on remodeling of human coronary artery transplants in severe combined immunodeficient mice. Bevacizumab ameliorated peripheral blood mononuclear cell-induced but not interferon-gamma-induced neointimal formation. This inhibitory effect was associated with a reduction in graft T-cell accumulation without affecting T-cell activation. VEGF enhanced T-cell capture by activated endothelium under flow conditions. The VEGF effect could be recapitulated when a combination of recombinant intercellular adhesion molecule 1 and vascular cell adhesion molecule-1 rather than endothelial cells was used to capture T cells. A subpopulation of CD3+ T cells expressed VEGF receptor (VEGFR)-1 by immunostaining and FACS analysis. VEGFR-1 mRNA was also detectable in purified CD4+ T cells and Jurkat and HSB-2 T-cell lines. Stimulation of HSB-2 and T cells with VEGF triggered downstream ERK phosphorylation, demonstrating the functionality of VEGFR-1 in human T cells.


CONCLUSIONS
VEGF contributes to vascular remodeling in human arteries through a direct effect on human T cells that enhances their recruitment to the vessel. These findings raise the possibility of novel therapeutic approaches to vascular remodeling based on inhibition of VEGF signaling.
Yale University School of Medicine, New Haven, Conn., USA.
Jiasheng
J
Zhang
Teresa
T
Silva
Timur
T
Yarovinsky
Thomas D
TD
Manes
Sina
S
Tavakoli
Lei
L
Nie
George
G
Tellides
Jordan S
JS
Pober
Jeffrey R
JR
Bender
Mehran M
MM
Sadeghi
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D001158:Arteries / Q000187:drug effects / Q000502:physiology*; D000068258:Bevacizumab; D017252:CD3 Complex / Q000276:immunology; D003331:Coronary Vessels / Q000637:transplantation*; D006801:Humans; D019169:Jurkat Cells; D008214:Lymphocytes / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D016513:Mice, SCID; D040262:Receptors, Vascular Endothelial Growth Factor / Q000235:genetics*; D013601:T-Lymphocytes / Q000276:immunology; D014183:Transplantation, Heterologous; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000494:pharmacology
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D017252:CD3 Complex; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D040262:Receptors, Vascular Endothelial Growth Factor