Review Article
Activated αvβ3 Integrin Targeting in Injury-Induced Vascular Remodeling

https://doi.org/10.1016/j.tcm.2006.07.003Get rights and content

There is currently no imaging modality to track the remodeling process, a common feature of a broad spectrum of vasculopathies, in vivo. αvβ3 Integrin is up-regulated in proliferating vascular cells. RP748, a novel peptidomimetic tracer, binds specifically to the activated αvβ3 conformer and exhibits favorable binding characteristics for in vivo imaging. In a model of injury-induced vascular remodeling in apoE null mice, RP748 localization to the injured carotid arteries parallels vascular cell proliferation, providing an opportunity to image the remodeling process in vivo.

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

References (41)

  • ZS Galis et al.

    Matrix metalloproteinases in vascular remodeling and atherogenesis: the good, the bad, and the ugly

    Circ Res

    (2002)
  • TD Harris et al.

    Design, synthesis, and evaluation of radiolabeled integral αvβ3 receptor antagonists for tumor imaging and radiotherapy

    Cancer Biother Radiopharm

    (2003)
  • R Haubner et al.

    Radiolabeled tracers for imaging of tumor angiogenesis and evaluation of anti-angiogenic therapies

    Curr Pharm Des

    (2004)
  • R Haubner et al.

    Radiolabeled alpha(v)beta3 integrin antagonists: a new class of tracers for tumor targeting

    J Nucl Med

    (1999)
  • R Haubner et al.

    Glycosylated RGD-containing peptides: tracer for tumor targeting and angiogenesis imaging with improved biokinetics

    J Nucl Med

    (2001)
  • R Haubner et al.

    Noninvasive imaging of αvβ3 integrin expression using 18F-labeled RGD-containing glycopeptide and positron emission tomography

    Cancer Res

    (2001)
  • M Hoshiga et al.

    Alpha-v beta-3 integrin expression in normal and atherosclerotic artery

    Circ Res

    (1995)
  • J Hua et al.

    Noninvasive imaging of angiogenesis with a 99mTc-labeled peptide targeted at alphavbeta3 integrin after murine hindlimb ischemia

    Circulation

    (2005)
  • LL Johnson et al.

    In vivo uptake of radiolabeled antibody to proliferating smooth muscle cells in a swine model of coronary stent restenosis

    J Nucl Med

    (2000)
  • S Kanda et al.

    Matrix metalloproteinase and alphavbeta3 integrin-dependent vascular smooth muscle cell invasion through a type I collagen lattice

    Arterioscler Thromb Vasc Biol

    (2000)
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