E-selectin is required for the antiangiogenic activity of endostatin.
Endostatin, a 20-kDa fragment of collagen XVIII, is a potent angiogenesis inhibitor. E-selectin, an inducible leukocyte adhesion molecule specifically expressed by endothelial cells, has also been implicated in angiogenesis. By using in vivo, ex vivo, and in vitro angiogenic assays, we investigated the functional relationship between endostatin and E-selectin. In corneal micropocket assays, recombinant endostatin administered i.p. by osmotic pump inhibited basic fibroblast growth factor-induced angiogenesis in WT, but not E-selectin-deficient, mice. Similarly, endostatin inhibited vascular endothelial growth factor-stimulated endothelial sprout formation from aortic rings dissected from WT but not from E-selectin-deficient mice. To further explore this apparent requirement for E-selectin in endostatin action, we manipulated E-selectin expression in cultured human endothelial cells. When E-selectin was induced by IL-1beta, or lipopolysaccharide, human umbilical vein endothelial cells and human dermal microvascular endothelial cells each became markedly more sensitive to inhibition by endostatin in a vascular endothelial growth factor-induced cell migration assay. To dissociate E-selectin expression from other consequences of endothelial activation, human umbilical vein endothelial cells were transduced with an adenoviral human E-selectin expression construct; these cells also showed increased sensitivity to endostatin, and this effect required the E-selectin cytoplasmic domain. Taken together, these results indicate that E-selectin is required for the antiangiogenic activity of endostatin in vivo and ex vivo and confers endostatin sensitivity to nonresponsive human endothelial cells in vitro. E-selectin may be a useful predictor and modulator of endostatin efficacy in antiangiogenic therapy.
Yu
Ying
Y
Vascular Biology Program, Department of Surgery, Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA. ying.yu@childrens.harvard.edu
Moulton
Karen S
KS
Khan
Mohamed K
MK
Vineberg
Sabrina
S
Boye
Eileen
E
Davis
Vannessa M
VM
O'Donnell
Peter E
PE
Bischoff
Joyce
J
Milstone
David S
DS
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement; D002478:Cells, Cultured; D003315:Cornea / Q000098:blood supply; D016207:Cytokines / Q000494:pharmacology; D019040:E-Selectin / Q000235:genetics / Q000378:metabolism*; D043169:Endostatins / Q000494:pharmacology*; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D017353:Gene Deletion; D018922:HL-60 Cells; D006801:Humans; D066298:In Vitro Techniques; D007962:Leukocytes / Q000166:cytology / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000187:drug effects; D012680:Sensitivity and Specificity; D014161:Transduction, Genetic; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
D020533:Angiogenesis Inhibitors; D016207:Cytokines; D019040:E-Selectin; D043169:Endostatins; D042461:Vascular Endothelial Growth Factor A