Review ArticleActivated αvβ3 Integrin Targeting in Injury-Induced Vascular Remodeling
Section snippets
Scope of the Problem
Vascular remodeling, broadly defined as an enduring change in the size and/or composition of adult blood vessels (Galis and Khatri 2002), is a common feature of a wide spectrum of vascular diseases (Table 1). Whether focal, as in atherosclerosis and postangioplasty restenosis, or diffuse, as in diabetes and graft arteriosclerosis (GA), pathological remodeling can lead to lumen loss and ischemia. Postangioplasty restenosis and GA are the prototypic clinical models of mechanical and immune
Biology of Remodeling
The two components of remodeling, that is, geometrical remodeling (the change in vessel size, whether inward or outward) and neointima formation, play distinct yet complementary roles in the pathogenesis. The hyperplastic response to arterial injury involves a cascade of events, including endothelial denudation, platelet deposition and activation, thrombus formation, and leukocyte recruitment and activation. Consequential secretion of growth and chemotactic factors ultimately leads to vascular
Molecular Imaging and Vascular Remodeling
Molecular nuclear imaging provides an opportunity for imaging the remodeling process in vascular pathology rather than simply anatomical changes. Targeted imaging of proliferating VSMC is a promising approach to early detection of remodeling. The feasibility of this approach has been demonstrated in a series of proof-of-principle experiments. In a vascular injury, high-lipid-fed rabbit model, Z2D3, an antibody to an unknown component of atherosclerotic plaque, localizes exclusively to
αvβ3 Integrin and Vascular Remodeling
Integrins, a family of heterodimeric cell surface glycoprotein adhesion molecules, mediate cell–extracellular matrix and cell–cell interactions. They are involved in a variety of biological processes such as cell adhesion, proliferation, migration, and differentiation. Each integrin recognizes a specific set of counterreceptors, most via an RGD-containing binding site. αvβ3 integrin is expressed by EC, VSMC, platelets, growth factor-stimulated monocytes, T lymphocytes, and osteoclasts (Shattil
Integrin Activation
The effects of stimulatory and inhibitory antibodies (e.g., mAb 8A2 for β1 integrins), coupled with the regulation of ligand binding by divalent cations, has led to a model of integrin-ligand binding that is dependent on conformational changes in integrin structure (Humphries 1996). These conformational changes may be recognized by monoclonal antibodies such as mAb 15/7 for β1 integrin, and AP5, LIBS-6, and 7G2 for β3 integrins, which can detect the active (ligand-binding) state of the
Characterization of Novel, αvβ3-Targeted Tracers
As noted above, αvβ3-targeted imaging of angiogenesis has been used to detect ischemia-induced myocardial (Meoli et al. 2004) and hind-limb (Hua et al. 2005) angiogenesis, as well as early stages of atherosclerosis by targeting vasa vasorum neovasculature (Winter et al. 2003). These tracers can be classified into several groups based on their chemical structure (peptidic versus nonpeptidic), imaging modality (SPECT [Haubner et al. 2001a], PET [Haubner et al. 2001b], near-infrared [Harris et al.
RP748 Binding Characteristics to Activated αvβ3 Integrin
Molecular imaging is founded on high-affinity, high-level, and specific binding of the tracer to target. It is believed that with the current instrumentation, 105–106 binding sites and affinities in the nmolar range are required for targeted nuclear imaging. We addressed the binding characteristics of RP748 to EC and the effect of integrin activation by radioimmunoassay and Scatchard analysis. Integrin activation with Mn2+ increased RP748 affinity for αvβ3 15-fold, with the Kd decreasing from
RP748 Uptake and Cell Proliferation in Vascular Remodeling
To address the ability of RP748 to track αvβ3 integrin activation in vivo, RP748 was injected to apoE −/− mice at different times after left common carotid injury. Tracer biodistribution and clearance were quantified by dynamic high-resolution planar imaging (with the use of a 1-mm aperture pinhole collimator and a SPECT camera [GE Millenium VG]) and serial blood sampling. In apoE−/− mouse, RP748 had a rapid renal clearance (Figure 2). Less than 0.5% of the RP748 injected dose was detectable in
Conclusions and Perspectives
Vascular remodeling is a feature of a broad spectrum of vasculopathies. Early detection of the remodeling process, especially with noninvasive imaging, can provide prognostic information and an opportunity for early therapeutic interventions. This may be achieved by molecular imaging, targeted at specific molecular markers of the remodeling process. αvβ3 integrin up-regulation and activation are early events within injury-induced vascular remodeling. Targeting the active conformation of the
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