Vascular endothelial growth factor enhances macrophage clearance of apoptotic cells.
Efficient clearance of apoptotic cells from the lung by alveolar macrophages is important for the maintenance of tissue structure and function. Lung tissue from humans with emphysema contains increased numbers of apoptotic cells and decreased levels of vascular endothelial growth factor (VEGF). Mice treated with VEGF receptor inhibitors have increased numbers of apoptotic cells and develop emphysema. We hypothesized that VEGF regulates apoptotic cell clearance by alveolar macrophages (AM) via its interaction with VEGF receptor 1 (VEGF R1). Our data show that the uptake of apoptotic cells by murine AMs and human monocyte-derived macrophages is inhibited by depletion of VEGF and that VEGF activates Rac1. Antibody blockade or pharmacological inhibition of VEGF R1 activity also decreased apoptotic cell uptake ex vivo. Conversely, overexpression of VEGF significantly enhanced apoptotic cell uptake by AMs in vivo. These results indicate that VEGF serves a positive regulatory role via its interaction with VEGF R1 to activate Rac1 and enhance AM apoptotic cell clearance.
National Jewish Health, Denver, CO 80206, USA. mark.kearns@ucdenver.edu
Mark T
MT
Kearns
Samay
S
Dalal
Sarah A
SA
Horstmann
Tiffany R
TR
Richens
Takeshi
T
Tanaka
Jenna M
JM
Doe
Darren M
DM
Boe
Norbert F
NF
Voelkel
Laimute
L
Taraseviciene-Stewart
William J
WJ
Janssen
Chun G
CG
Lee
Jack A
JA
Elias
Donna
D
Bratton
Rubin M
RM
Tuder
Peter M
PM
Henson
R William
RW
Vandivier
D000818:Animals; D000911:Antibodies, Monoclonal; D017209:Apoptosis; D002460:Cell Line; D004318:Doxycycline / Q000008:administration & dosage / Q000494:pharmacology; D004646:Emphysema / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology; D019169:Jurkat Cells; D008168:Lung / Q000166:cytology / Q000378:metabolism*; D016676:Macrophages, Alveolar / Q000276:immunology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000378:metabolism*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000276:immunology / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D007211:Indoles; D011758:Pyrroles; C107953:RAC1 protein, human; D042461:Vascular Endothelial Growth Factor A; C116890:Semaxinib; D040281:Vascular Endothelial Growth Factor Receptor-1; D020830:rac1 GTP-Binding Protein; D004318:Doxycycline