title: Activation of integrin receptors is required for growth factor-induced smooth muscle cell dysfunction.
abstract: OBJECTIVE
  Growth factors and cytokines such as platelet-derived growth factor (PDGF), epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), and transforming growth factor beta (TGF-beta) stimulate smooth muscle cell (SMC) proliferation and extracellular matrix (ECM) protein production by binding and activating their respective receptors. Recent investigations suggest that simultaneous activation of integrins, which are heterodimeric receptors for ECM, may also be required for growth factor and cytokine function. In this study, we tested the hypothesis that activation of two integrins, alpha v beta 3 and alpha 2 beta 1, both previously identified in vascular SMCs, is necessary for growth factor- and cytokine-induced vascular SMC dysfunction.
  
  
  METHODS
  DNA synthesis was measured after stimulation of SMCs derived from human saphenous vein with the growth factors PDGF-BB, EGF, and bFGF. SMC fibronectin (Fn) production was measured (by means of Western blotting) in SMCs stimulated for 72 hours with TGF-beta1 or EGF. Both endpoints were measured in the presence and absence of antibodies that block the function of the alpha v beta 3 and alpha 2 beta 1 integrins as well as the alpha2 and beta1 subunits.
  
  
  RESULTS
  The alpha v beta 3 integrin blocking antibody significantly inhibited PDGF-BB-, EGF-, and bFGF-induced SMC proliferation. The alpha v beta 3 integrin antibody also markedly inhibited TGF-1- and EGF-induced SMC Fn production. Neither the alpha 2 beta 1 integrin nor the alpha2 or the beta1 subunits inhibited either proliferation or matrix protein production in response to any of these agonists.
  
  
  CONCLUSIONS
  The alpha v beta 3 integrin is required for growth factor- and cytokine-induced SMC proliferation and FN production, whereas alpha 2 beta 1 is not. Since activation of alpha v beta 3 is required for the activity of at least four distinct growth factors and cytokines, inhibition of this integrin might be used as a therapeutic tool for the prevention of intimal hyperplasia.
authors.affiliation: Department of Surgery, Division of Vascular Surgery, New York Presbyterian Hospital/Weill Medical College, Cornell Campus, New York, NY 10021, USA.
authors.forename: K
authors.initials: K
authors.lastname: Mawatari
authors.forename: B
authors.initials: B
authors.lastname: Liu
authors.forename: K C
authors.initials: KC
authors.lastname: Kent
mesh_terms: D019138:Antibodies, Blocking / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis / Q000187:drug effects; D003864:Depression, Chemical; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D005353:Fibronectins / Q000096:biosynthesis / Q000187:drug effects; D006801:Humans; D016023:Integrins / Q000187:drug effects* / Q000276:immunology / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D019038:Platelet Glycoprotein GPIb-IX Complex; D010980:Platelet Membrane Glycoproteins; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D011956:Receptors, Cell Surface / Q000187:drug effects* / Q000502:physiology; D011994:Recombinant Proteins / Q000494:pharmacology; D012501:Saphenous Vein / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D013268:Stimulation, Chemical
chemical_list: D019138:Antibodies, Blocking; D005353:Fibronectins; D016023:Integrins; D019038:Platelet Glycoprotein GPIb-IX Complex; D010980:Platelet Membrane Glycoproteins; D010982:Platelet-Derived Growth Factor; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; C032193:glycoprotein receptor GPIb-IX; D016222:Fibroblast Growth Factor 2; D004815:Epidermal Growth Factor; D004247:DNA