Targeted disruption of endothelial cell-selective adhesion molecule inhibits angiogenic processes in vitro and in vivo.
Endothelial cell-selective adhesion molecule (ESAM) is a member of the immunoglobulin receptor family that mediates homophilic interactions between endothelial cells. To address potential in vivo angiogenic functions of this molecule, mice lacking ESAM (ESAM-/-) were generated by gene-targeted deletion. ESAM-/- mice did not show overt morphological defects in the vasculature. To evaluate the role of ESAM in pathological angiogenesis, wild type (WT) and ESAM-/- mice were injected with melanoma and Lewis lung carcinoma cells. By 14 days after injection, tumor volumes of B16F10 and LL/2 in ESAM-/- mice were 48 and 37% smaller, respectively, compared with WT mice. Vascular density of the tumors, as determined by CD31 staining, was also decreased in the ESAM null animals. Matrigel plug assays showed less neovascularization in ESAM-/- mice than in WT mice. ESAM-/- endothelial cells exhibited less in vitro tube formation and decreased migration in response to basic fibroblast growth factor when compared with WT cells, and endothelial-like yolk sac cells engineered to overexpress ESAM showed accelerated tube formation in vitro. These in vitro and in vivo studies suggest that ESAM has a redundant functional role in physiological angiogenesis but serves a unique and essential role in pathological angiogenic processes such as tumor growth.
Ishida
Tatsuro
T
Donald W. Reynolds Cardiovascular Clinical Research Center, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
Kundu
Ramendra K
RK
Yang
Eugene
E
Hirata
Ken-ichi
K
Ho
Yen-Dong
YD
Quertermous
Thomas
T
D000818:Animals; D001672:Biocompatible Materials / Q000494:pharmacology; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000737:chemistry* / Q000235:genetics*; D002465:Cell Movement; D003001:Cloning, Molecular; D003094:Collagen / Q000494:pharmacology; D018076:DNA, Complementary / Q000378:metabolism; D004338:Drug Combinations; D004727:Endothelium / Q000166:cytology*; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D019793:Fluorescein / Q000494:pharmacology; D017353:Gene Deletion; D007797:Laminin / Q000494:pharmacology; D008546:Melanoma, Experimental; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D008957:Models, Genetic; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000096:biosynthesis; D011485:Protein Binding; D011509:Proteoglycans / Q000494:pharmacology; D013997:Time Factors; D014407:Tumor Cells, Cultured
D001672:Biocompatible Materials; D015815:Cell Adhesion Molecules; D018076:DNA, Complementary; D004338:Drug Combinations; C428190:Esam protein, mouse; D007797:Laminin; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011509:Proteoglycans; D016222:Fibroblast Growth Factor 2; C059485:matrigel; D003094:Collagen; D019793:Fluorescein