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(Circulation. 2004;110:84-90.)
© 2004 American Heart Association, Inc.

Original Articles

Detection of Injury-Induced Vascular Remodeling by Targeting Activated _vß₃ Integrin In Vivo

Mehran M. Sadeghi, MD; Svetlana Krassilnikova, MD; Jiasheng Zhang, MD; Amir A. Gharaei, MD; Hooman Rastegar Fassaei, MD; Leila Esmailzadeh, MS; Ali Kooshkabadi; Scott Edwards, PhD; Padmaja Yalamanchili, PhD; Thomas D. Harris, PhD; Albert J. Sinusas, MD; Barry L. Zaret, MD; Jeffrey R. Bender, MD

From the Raymond and Beverly Sackler Cardiovascular Molecular Imaging Laboratory, Section of Cardiovascular Medicine (M.M.S., S.K., J.Z., A.A.G., H.R.F., L.E., A.K., A.J.S., B.L.Z., J.R.B.), Yale University School of Medicine, New Haven, Conn; VA Connecticut Healthcare System (M.M.S., S.K., J.Z., A.A.G., H.R.F., L.E., A.K.), West Haven, Conn; and Bristol-Myers Squibb Medical Imaging (S.E., P.Y., T.D.H.), North Billerica, Mass.

Correspondence to Mehran M. Sadeghi, MD, VA Connecticut Healthcare System, 950 Campbell Ave, 111B, West Haven, CT 06516. E-mail mehran.sadeghi{at}yale.edu

Received June 13, 2003; de novo received December 4, 2003; revision received February 23, 2004; accepted March 11, 2004.

Background— The _vß₃ 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 _vß₃ integrin expression in vivo.

Methods and Results— RP748, a novel ¹¹¹In-labeled _vß₃-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 _vß₃ at focal contacts. Activation of _vß₃ 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 _v and ß₃ 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 _vß₃ integrin and can track the injury-induced vascular proliferative process in vivo.

Key Words: imaging • nuclear medicine • arteries • restenosis

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