Atherosclerosis 154 (2001) 377 – 385 Inflammatory cytokines stimulate vascular smooth muscle cells locomotion and growth by enhancing 51 integrin expression and function Giovanni Barillari a, *, Loredana Albonici a , Sandra Incerpi b , Laura Bogetto b , Giuseppa Pistritto a , Antonio Volpi a , Barbara Ensoli c , Vittorio Manzari a a Department of Experimental Medicine, Uniersity ‘Tor Vergata’, 00133 Rome, Italy b Department of Biology, Uniersity ‘Tor Vergata’, 00133 Rome, Italy c Istituto Superiore di Sanita ` , 00161 Rome, Italy Received 8 November 1999; received in revised form 29 March 2000; accepted 17 April 2000 Abstract The formation of atherosclerotic lesions requires the migration of vascular smooth muscle cells from the media into the intima of the artery and their proliferation. These events, which are preceded and accompanied by inflammation, are modulated by integrin receptors linking vascular smooth muscle cells to extracellular matrix molecules. Among them, fibronectin induces vascular smooth muscle cells to acquire the phenotype they show in the atherosclerotic plaque. Here we show that amounts of interleukin-1 , tumor necrosis factor  and interferon- as possibly released by activated immune cells infiltrating atherosclerotic lesions, upregulate vascular smooth muscle cell expression of the 51 integrin, a fibronectin receptor. This improves vascular smooth muscle cell capability of migrating toward soluble or anchored fibronectin and of adhering to immobilized fibronectin. The latter effect, in turn, augments vascular smooth muscle cell proliferative response to mitogens, as suggested by the increase of intracellular pH. Finally, the effects that inflammatory cytokines have on vascular smooth muscle cell locomotion and growth, are specifically blocked by anti-51 antibodies. As fibronectin and 51 levels are augmented in vivo in the atherosclerotic plaques, these findings support the use of integrin antagonists as potential adjuvants in atherosclerosis treatment. © 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Atherogenesis; Inflammation; Fibronectin; Integrins; Integrin antagonists www.elsevier.com/locate/atherosclerosis 1. Introduction Migration of vascular smooth muscle cells (VSMC) from the media to the intima and proliferation of intimal VSMC are key early events in atherosclerotic lesion development [1]. Although triggered by soluble chemotactic and growth factors, cellular migration and growth are mod- ulated by the interactions occurring between cells and extracellular matrix molecules [2]. It is of interest that one of the characteristics that accompanies atherosclerotic lesion development is a dramatic change in the composition of the extracellular matrix of the vascular wall. This is expressed by a marked increase in fibronectin, a blood vessel wall component that is necessary for the integrity of the vasculature [3]. The fibronectin increase occurring in atherogenesis is due both to the augmented fibronectin synthesis by vascular cells and to the deposition of soluble, plasmatic fibronectin on damaged endothelial membrane [3,4]. Fibronectin has profounds effects on VSMC physiol- ogy. In particular, when normal VSMC are plated on fibronectin they switch from the ‘contractile’, non-pro- liferative phenotype to the ‘synthetic’, highly prolifera- tive phenotype, which is the same as shown by VSMC Abbreiations: bFGF, basic fibroblast growth factor; IFN, inter- feron; IL, interleukin; pHi, intracellular pH; TNF, tumor necrosis factor; VSMC, vascular smooth muscle cells. * Corresponding author. Tel.: +39-06-72596510; fax: +39-06- 72596506. 0021-9150/01/$ - see front matter © 2001 Elsevier Science Ireland Ltd. All rights reserved. PII: S0021-9150(00)00506-2