Mechanism by which H-2g, a glucose analog of blood group H antigen, mediates angiogenesis.
The 4A11 antigen is a unique cytokine-inducible antigen up-regulated on rheumatoid arthritis (RA) synovial endothelial cells (ECs) compared with normal ECs. Previously, we showed that in soluble form, this antigen, Lewis(y)-6/H-5-2 (Le(y)/H) or its glucose analog, 2-fucosyl lactose (H-2g), induced the expression of EC intercellular adhesion molecule-1 (ICAM-1) and leukocyte-endothelial adhesion through the Janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) pathway. Currently, we show that H-2g induces release of EC angiogenic basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), an effect inhibited by decoy nuclear factor kappaB (NFkappaB) oligodeoxynucleotide (ODN). JAK2 and phosphoinositide-3 kinase (PI3K) are 2 upstream kinases of NFkappaB activated by H-2g, as confirmed by an inhibitor of kappa B kinase (IKKbeta) assay. In vitro, H-2g induces vascular sprouting in the rat aortic ring model, whereas blockade of JAK2, PI3K, or NFkappaB inhibits sprouting. Likewise, in the in vivo mouse Matrigel plug angiogenesis assay, chemical inhibitors and antisense or decoy ODNs of JAK2, PI3K, or NFkappaB decrease angiogenesis, confirming the importance of these pathways in H-2g-induced EC signaling. The critical role of Le(y)/H involvement in angiogenesis and its signaling pathways may provide new targets for therapy of diseases characterized by pathologic neovascularization.
Zhu
Kui
K
Department of Medicine, Northwestern University of Feinberg School of Medicine, Chicago, IL, USA.
Amin
Mohammed Asif
MA
Zha
Yuanyuan
Y
Harlow
Lisa A
LA
Koch
Alisa E
AE
D000017:ABO Blood-Group System; D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D004187:Disaccharides / Q000494:pharmacology*; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D016222:Fibroblast Growth Factor 2 / Q000096:biosynthesis; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D007983:Lewis Blood Group Antigens / Q000494:pharmacology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D010770:Phosphotransferases / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis; D014661:Vasoconstriction / Q000187:drug effects
D000017:ABO Blood-Group System; D004187:Disaccharides; D007983:Lewis Blood Group Antigens; D016328:NF-kappa B; D009838:Oligodeoxyribonucleotides; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C112685:fucosyl-1-2-galactose; D016222:Fibroblast Growth Factor 2; D018799:Intercellular Adhesion Molecule-1; D010770:Phosphotransferases