Integrin alpha2beta1 is the required receptor for endorepellin angiostatic activity.
Endorepellin, the C-terminal module of perlecan, has angiostatic activity. Here we provide definitive genetic and biochemical evidence that the functional endorepellin receptor is the alpha2beta1 integrin. Notably, the specific endorepellin binding to the receptor was cation-independent and was mediated by the alpha2 I domain. We show that the anti-angiogenic effects of endorepellin cannot occur in the absence of alpha2beta1. Microvascular endothelial cells from alpha2beta1(-/-) mice, but not those isolated from either wild-type or alpha1beta1(-/-) mice, did not respond to endorepellin. Moreover, syngeneic Lewis lung carcinoma xenografts in alpha2beta1(-/-) mice failed to respond to systemic delivery of endorepellin. In contrast, endorepellin inhibited tumor growth and angiogenesis in the wild-type mice expressing integrin alpha2beta1. We conclude that the angiostatic effects of endorepellin in vivo are mediated by a specific interaction of endorepellin with the alpha2beta1 integrin receptor.
Woodall
Benjamin P
BP
Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Nyström
Alexander
A
Iozzo
Rex A
RA
Eble
Johannes A
JA
Niland
Stephan
S
Krieg
Thomas
T
Eckes
Beate
B
Pozzi
Ambra
A
Iozzo
Renato V
RV
D043165:Angiostatic Proteins / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D005260:Female; D019812:Heparan Sulfate Proteoglycans / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D039222:Integrin alpha1beta1 / Q000235:genetics / Q000378:metabolism; D038982:Integrin alpha2beta1 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D014183:Transplantation, Heterologous
D043165:Angiostatic Proteins; D019812:Heparan Sulfate Proteoglycans; D039222:Integrin alpha1beta1; D038982:Integrin alpha2beta1; D010446:Peptide Fragments; C498861:endorepellin protein, mouse; C071927:perlecan