αvβ3, αvβ5, and osteopontin are coordinately upregulated at early time points in a rabbit model of neointima formation

Abstract

Both smooth muscle cell migration and replication are known to be responsible for neointima formation. Recent reports based on in vitro studies and animal models of neointima formation highlight the possible importance of alphavbeta3 and alphavbeta5 integrins in mediating neointima formation. Clinical data suggest that specific alphavbeta3 blockade may limit restenosis. The aim of this study was to identify the expression of alphavbeta3 and alphavbeta5 and their ligand osteopontin in the very early phases of neointima formation in a rabbit model. A non-occlusive cuff placed around the rabbit femoral artery resulted in a complete, concentric neointima that formed by 14 days. Antibodies specific for the integrin heterodimers and for osteopontin, along with a probe specific for osteopontin mRNA, were used to identify expression at early time points (6 h, 1 day, 3 days, 5 days) post-cuffing. Immunohistochemistry and in situ hybridization expression results were quantitated by image analysis and tested for statistical significance by a two-tailed t-test. The data demonstrated the rapid (within 6 h) and abundant upregulation of alphavbeta3 and alphavbeta5 integrins and their ligand during very early time points of neointima formation. The very early (6 h) upregulation of alphavbeta3 underscores a potentially important clinical intervention point in limiting restenosis following clinical angioplasty procedures.

The Role of Src Kinase in Insulin-like Growth Factor-dependent Mitogenic Signaling in Vascular Smooth Muscle Cells

“…Several studies have shown that a variety of cell types utilize Shc activation in response to IGF-I to signal to MAP kinase (3,5,6,9,15,36,37,49,50), and in some cell types IRS-1-mediated signaling has been shown to be down-regulated in response to stress or changes in nutrient availability (51,52). However, the frequency with which this pathway is activated selectively during normal growth in vivo or whether its role is limited to pathophysiologic states such as following vascular injury has not been determined (53).…”

Implication of allelic polymorphism of osteopontin in the development of lupus nephritis in MRL/lpr mice

“…Indeed, the Tyr 261 and the Asp 172 correspond to a heparin binding site and a phosphorylation site overlapped by the homologous Itga 4 b 1 binding site of fibronectin, respectively [15]. Asn 126 neighbors the RGDS motif that serves as a binding site for Itga v b 1 [36], a v b 3 [37], and a v b 5 [38]. The critical substitutions for the functional differences of allelic OPNs need to be identified.…”

Targeting of αv integrins interferes with FAK activation and smooth muscle cell migration and invasion

“…Immediately after the intervention, an early inflammatory response characterized by the recruitment and adhesion of leucocytes, macrophages, and activated platelets to the site of the vessel injury can be observed. In addition to various growth factors and cytokines released locally by resident and recruited cells, plasma proteins such as vitronectin, osteopontin, and fibronectin are deposited at the site of the lesion [4][5][6][7]. A combination of these chemotactic and haptotactic stimuli drives the proliferation and migration of vascular cells, mainly smooth muscle cells (SMCs), leading to their accumulation in the newly formed neointima.…”