Expression of antisense to integrin subunit beta 3 inhibits microvascular endothelial cell capillary tube formation in fibrin.
alpha(v)beta(3) antagonists are potent angiogenesis inhibitors, and several different classes of inhibitors have been developed, including monoclonal antibodies, synthetic peptides, and small organic molecules. However, each class of inhibitor works by the same principal, by blocking the binding of ligands to alpha(v)beta(3). In an effort to develop an alpha(v)beta(3) inhibitor that down-regulates the actual level of alpha(v)beta(3), we developed an antisense strategy to inhibit alpha(v)beta(3) expression in vitro. beta(3) antisense expressed in endothelial cells specifically down-regulated alpha(v)beta(3) and inhibited capillary tube formation, with the extent of down-regulation correlating with the extent of tube formation inhibition. This inhibition was matrix-specific, since tube formation was not inhibited in Matrigel. These findings support the notion that alpha(v)beta(3) is required for an essential step of angiogenesis in fibrin, namely capillary tube formation. These results suggest that pseudogenetic inhibition of beta(3) integrins using antisense techniques may ultimately provide a therapeutic means to inhibit angiogenesis in vivo.
Department of Biochemistry and Molecular Biology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA.
S M
SM
Dallabrida
M A
MA
De Sousa
D H
DH
Farrell
D020533:Angiogenesis Inhibitors / Q000235:genetics / Q000502:physiology; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D015153:Blotting, Western; D002196:Capillaries / Q000166:cytology / Q000187:drug effects / Q000254:growth & development* / Q000648:ultrastructure; D002460:Cell Line; D003094:Collagen / Q000378:metabolism; D020405:Dermis / Q000098:blood supply; D015536:Down-Regulation; D004338:Drug Combinations; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000254:growth & development* / Q000648:ultrastructure; D005337:Fibrin / Q000378:metabolism* / Q000648:ultrastructure; D015870:Gene Expression; D015316:Genetic Therapy; D006801:Humans; D007797:Laminin / Q000378:metabolism; D008854:Microscopy, Electron; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000628:therapy; D018919:Neovascularization, Physiologic / Q000187:drug effects; D016133:Polymerase Chain Reaction; D011509:Proteoglycans / Q000378:metabolism; D016372:RNA, Antisense / Q000235:genetics / Q000502:physiology* / Q000627:therapeutic use; D019030:Receptors, Vitronectin / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D014162:Transfection
D020533:Angiogenesis Inhibitors; D000906:Antibodies; D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; D016372:RNA, Antisense; D019030:Receptors, Vitronectin; C059485:matrigel; D005337:Fibrin; D003094:Collagen