Copyright © 2005, European Society of Cardiology
Role of integrins, including 
8, for neointima formation after vascular injury
Department of Pathology, School of Medicine, Fukuoka University, Nanakuma 7-45-1 Jonan-ku, Fukuoka city, Fukuoka, 814-0180, Japan
* Corresponding author. Tel.: +81 92 801 1011x3285; fax: +81 92 863 8383. Email address: nysakata{at}fukuoka-u.ac.jp
Received 28 December 2004; accepted 5 January 2005
See article by Z. Zangham and G. Thibault [15] (pages 813–822) in this issue.
Restenosis secondary to intimal hyperplasia is a serious complication of percutaneous transluminal coronary angioplasty, which is caused by smooth muscle cell (SMC) migration and proliferation within the neointima of coronary arteries. The principle function of vascular SMCs (VMSCs) is to maintain vascular tone and resistance. Differentiated SMCs exhibit a contractile phenotype that is characterized by smooth muscle (SM)-specific contractile and cytoskeletal proteins [1]. The other important function of SMCs is related to the response to the repair of the blood vessel wall after vascular injury [1,2]. These responses require modulation of the SM phenotype and synthetic and migratory activities of SMCs, which necessitate an alteration of adhesion receptors that anchor cells to the extracellular matrix (ECM) during cell contraction [2]. Integrins are the principle receptors for the ECM and serve as a transmembrane linkage between the ECM and the actin cytoskeleton. Integrins are composed of 
and β subunits. Each β combination has its own ligand binding specificity [3] and signalling properties [4]. Most integrins recognize several ECM proteins [5]. Conversely, individual matrix proteins, such as fibronectin, laminin, collagens, osteopontin, and vitronectin, bind to several integrins [5].
Normal VSMCs exhibit predominantly activated β1 integrin [6], and 1, 3, 5 [7,8], 5β1, and 7β1 are also observed in the differentiated phenotype [5]. VSMCs that have been injured due to vascular injury show reduced expression of total and activated β1 integrin and increased expression of integrins 1β1, 5β1 and vβ3. Among these, vβ3 integrin seems to have a more important role for neointimal proliferation. Although vβ3 integrin is expressed both in normal and diseased blood vessels, some ECM ligands of vβ3 (thrombospondin, vitronectin, osteopontin, fibrin, and fibrinogen) are found only in injured or diseased blood vessels [5]. Furthermore, this integrin is also involved in transmembrane signalling. Thus, vβ3 has a profound effect on migration, proliferation, and apoptosis of SMCs in vascular injury. The role of β3 integrin for human neointimal proliferation has been investigated, and it was found that blocking the β3 integrin attenuated SMC accumulation in the neointima after balloon angioplasty in animals [9]. Since Abciximab, a blocking antibody for the β3 integrin subunit, improved clinical outcome after coronary balloon angioplasty, it was speculated that β3 integrin blockade might have contributed to the inhibition of intimal hyperplasia, leading to less luminal narrowing in these patients [10].
Compared to these intensive studies of integrins vβ3, 1β1, and 5β1, there has not been any study of 8 integrin with relation to neointima formation after vascular injury. The 8 integrin was originally described in the chick nervous system by Bossy et al. in 1991 [11]. In the mammalian adult, the 8 integrin is highly expressed in neuronal and mesenchymal cells, including vascular and visceral smooth muscle cells, alveolar myofibroblasts, and glomerular mesangial cells [11]. The 8 integrin was found to be associated only with the β1 integrin. 8β1 integrin is a receptor for fibronectin, vitronectin, tenascin C, osteopontin, nephronectin, and POEM [12]. The role of 8 integrin is still unclear, but increased expression of 8 integrin in animal models is observed in cardiac fibroblasts, pulmonary and hepatic fibrosis, and extensive renal interstitial fibrosis in the DOCA-salt model of hypertension, while fibroblasts in the interstitium of a normal kidney never express 8 integrin [12]. These findings are suggestive of an involvement of 8 integrin in extracellular matrix deposition. The 8 integrin was shown to promote cell attachment, spreading, and neural outgrowth. The cells in which 8 integrin is located have contractile potential. VSMCs in the normal, uninjured vessel stain intensely for 8 integrin. The 8 integrin is also important for kidney development. 8 integrin-deficient (8–/–) mice demonstrate a reduction in renal mass that can range from complete renal agenesis to the development of kidneys that are only slightly smaller than wild-type kidneys. However, histological changes that have been described are mildly increased glomerular matrix and dilatation of capillaries [13]. Mesangial cells from 8 integrin-deficient mice showed reduced attachment of fibronectin and vitronectin but migrated more easily and displayed an increased proliferative response on fibronectin or vitronectin compared to wild-type cells [14].
In the current issue of Cardiovascular Research, Zargham and Thibault have focused on the role of decreased expression of 8 integrin in vascular injury [15]. The authors found reduced expression of 8 and β1 integrin in the neointima after carotid artery injury. Cultured VSMCs revealed diminished 8 integrin after stimulation with PDGF, which promotes the migratory state, but not after angiotensin II, which induces the contractile state. Moreover, cultured VSMCs, which reduced 8 integrin by 70% after transfection with short interference mRNA, showed a significant increase of migration, but no proliferation. Based on these findings, the authors suggested that diminished expression of 8 integrin contributes to neointima formation after vascular injury. This is the first study to investigate the role of 8 integrin in neointima formation after vascular injury. The interesting point of the study is that it investigates the decreased expression of 8 integrin and the increased cell migration, while other integrins are upregulated in the neointima. Although the present study does not prove the mechanistic relationship between SMC migration and the decreased expression of 8 integrin, it does provide a new insight into neointimal proliferation after vascular injury.
There is some limitation in the present study and other animal model studies for investigating the induction of neointima formation of the carotid arteries by balloon denudation. The removal of intimal atheromatous plaque of the carotid arteries is a generally accepted technique used in humans that inevitably causes medial damage. However, restenosis occurs in a rather limited number of these arteries and requires additional risk factors, including hypertension, hyperlipidemia, and diabetes mellitus. The difference of the restenosis rate between the coronary and carotid arteries can be explained by more rapid blood stream and high blood pressure in the latter arteries. In the present study, neointimal thickening of the carotid arteries does not continue and even decreases at 4 weeks after injury. For restenosis secondary to coronary angioplasty, studies on the carotid artery may therefore be of only limited relevance.
All but one study of 8 integrin have been limited to animal models or cells in culture. Only one study has investigated the expression of 8 integrin in several human tissues but it did not explore its role in human pathophysiology [16]. Further studies will be needed to obtain more information on the role of 8 integrin in neointima formation in human arteries.
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