Loss of myeloid cell-derived vascular endothelial growth factor accelerates fibrosis.
Tissue injury initiates a complex series of events that act to restore structure and physiological homeostasis. Infiltration of inflammatory cells and vascular remodeling are both keystones of this process. However, the role of inflammation and angiogenesis in general and, more specifically, the significance of inflammatory cell-derived VEGF in this context are unclear. To determine the role of inflammatory cell-derived VEGF in a clinically relevant and chronically inflamed injury, pulmonary fibrosis, we deleted the VEGF-A gene in myeloid cells. In a model of pulmonary fibrosis in mice, deletion of VEGF in myeloid cells resulted in significantly reduced formation of blood vessels; however, it causes aggravated fibrotic tissue damage. This was accompanied by a pronounced decrease in epithelial cell survival and a striking increase in myofibroblast invasion. The drastic increase in fibrosis following loss of myeloid VEGF in the damaged lungs was also marked by increased levels of hypoxia-inducible factor (HIF) expression and Wnt/beta-catenin signaling. This demonstrates that the process of angiogenesis, driven by myeloid cell-derived VEGF, is essential for the prevention of fibrotic damage.
Molecular Biology Section, Division of Biological Sciences, University of California, San Diego, CA 92093, USA.
Christian
C
Stockmann
Yann
Y
Kerdiles
Marc
M
Nomaksteinsky
Alexander
A
Weidemann
Norihiko
N
Takeda
Andrew
A
Doedens
Antonio X
AX
Torres-Collado
Luisa
L
Iruela-Arispe
Victor
V
Nizet
Randall S
RS
Johnson
D000818:Animals; D001761:Bleomycin / Q000633:toxicity; D005260:Female; D017353:Gene Deletion; D000860:Hypoxia / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D010766:Phosphorylation; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
D042461:Vascular Endothelial Growth Factor A; D051176:beta Catenin; D001761:Bleomycin; D040301:Vascular Endothelial Growth Factor Receptor-2