Pathological neovascularization is reduced by inactivation of ADAM17 in endothelial cells but not in pericytes

Gisela Weskamp, Karen Mendelson, Steve Swendeman, Sylvain Le Gall, Yan Ma, Stephen Lyman, Akinari Hinoki, Satoru Eguchi, Victor Guaiquil, Keisuke Horiuchi, Carl P. Blobel

Research output: Contribution to journalArticlepeer-review

124 Citations (Scopus)


Rationale: 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. Methods and 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.

Original languageEnglish
Pages (from-to)932-940
Number of pages9
JournalCirculation research
Issue number5
Publication statusPublished - Mar 19 2010
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine


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