Pathological neovascularization is reduced by inactivation of ADAM17 in endothelial cells but not in pericytes.
BACKGROUND
Pathological neovascularization is a critical component of diseases such as proliferative retinopathies, cancer and rheumatoid arthritis, yet much remains to be learned about the underlying causes. Previous studies showed that vascular endothelial growth factor (VEGF)-A activates the membrane-anchored metalloproteinase ADAM17 (a disintegrin and metalloproteinase 17) in endothelial cells, thereby stimulating crosstalk between VEGF receptor 2 and extracellular signal-regulated kinase. These findings raised interesting questions about the role of ADAM17 in angiogenesis and neovascularization in vivo.


OBJECTIVE
The objective of this study was to inactivate ADAM17 in endothelial cells or in pericytes to determine how this affects developmental angiogenesis, pathological retinal neovascularization and heterotopic tumor growth.


RESULTS
We generated animals in which floxed ADAM17 was removed by Tie2-Cre in endothelial cells, or by smooth muscle (sm) Cre in smooth muscle cells and pericytes. There were no evident developmental defects in either conditional knockout strain, but pathological retinal neovascularization and growth of heterotopically injected tumor cells was reduced in Adam17flox/flox/Tie2-Cre mice, although not in Adam17flox/flox/sm-Cre mice. Moreover, lack of ADAM17 in endothelial cells decreased ex vivo chord formation, and this could be largely restored by addition of the ADAM17 substrate HB-EGF (heparin-binding epidermal growth factor-like growth factor). Finally we found that ADAM17 is important for the VEGF receptor 2 stimulated processing of several receptors with known functions in endothelial cell biology.


CONCLUSIONS
These results provide the first evidence for a role for ADAM17 in pathological neovascularization in vivo. Because ADAM17 does not appear to be required for normal developmental angiogenesis or vascular homeostasis, it could emerge as a good target for treatment of pathological neovascularization.
Weskamp
Gisela
G
Arthritis and Tissue Degeneration Program, Caspary Research Building, Room 426, Hospital for Special Surgery, 535 E 70th St, New York, NY 10021, USA.
Mendelson
Karen
K
Swendeman
Steve
S
Le Gall
Sylvain
S
Ma
Yan
Y
Lyman
Stephen
S
Hinoki
Akinari
A
Eguchi
Satoru
S
Guaiquil
Victor
V
Horiuchi
Keisuke
K
Blobel
Carl P
CP
D051722:ADAM Proteins / Q000172:deficiency* / Q000235:genetics; D000072198:ADAM17 Protein; D000199:Actins / Q000378:metabolism; D000818:Animals; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000201:enzymology*; D066257:Heparin-binding EGF-like Growth Factor; D019426:Integrases / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008546:Melanoma, Experimental / Q000098:blood supply* / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control*; D020286:Pericytes / Q000201:enzymology*; D011401:Promoter Regions, Genetic; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D042787:Receptor, TIE-2; D015861:Retinal Neovascularization / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control*; D013552:Swine; D013997:Time Factors; D047368:Tumor Burden; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
D000199:Actins; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D042461:Vascular Endothelial Growth Factor A; D020794:Receptor Protein-Tyrosine Kinases; D042787:Receptor, TIE-2; C079086:Tek protein, mouse; D040301:Vascular Endothelial Growth Factor Receptor-2; C045073:Cre recombinase; D019426:Integrases; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse