Detection of injury-induced vascular remodeling by targeting activated αvβ3 integrin in vivo

Background - The alpha(v)beta(3) integrin plays a critical role in cell proliferation and migration. We hypothesized that vascular cell proliferation, a hallmark of injury-induced remodeling, can be tracked by targeting alpha(v)beta(3) integrin expression in vivo. Methods and Results - RP748, a novel In-111-labeled alpha(v)beta(3)-specific radiotracer, was evaluated for its cell-binding characteristics and ability to track injury-induced vascular proliferation in vivo. Three groups of experiments were performed. In cultured endothelial cells (ECs), TA145, a cy3-labeled homologue of RP748, localized to alpha(v)beta(3) at focal contacts. Activation of alpha(v)beta(3) by Mn2+ led to increased EC binding of TA145. Left common carotid artery wire injury in apolipoprotein E-/- mice led to vascular wall expansion over a period of 4 weeks. RP748 (7.4 MBq) was injected into groups of 9 mice at 1, 3, or 4 weeks after left carotid injury, and carotids were harvested for autoradiography. Relative autographic intensity, defined as counts/pixel of the injured left carotid area divided by counts/pixel of the uninjured right carotid area, was higher at 1 and 3 weeks (1.8 +/- 0.1 and 1.9 +/- 0.2, respectively) and decreased significantly by 4 weeks after injury (1.4 +/- 0.1, P < 0.05). Carotid alpha(v) and beta(3) integrin expression was maximal at 1 week and decreased by 4 weeks after injury. The proliferation index, as determined by Ki67 staining, followed a temporal pattern similar to that of RP748 uptake. Dynamic gamma imaging demonstrated rapid renal clearance of RP748. Conclusions - RP748 has preferential binding to activated alpha(v)beta(3) integrin and can track the injury-induced vascular proliferative process in vivo.