Published Online
on June 21, 2004

A more recent version of this article appeared on July 6, 2004

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Submitted on June 13, 2003
Revised on February 23, 2004
Accepted on March 11, 2004

Detection of Injury-Induced Vascular Remodeling by Targeting Activated _v3 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, and 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.

^* To whom correspondence should be addressed. E-mail: mehran.sadeghi{at}yale.edu.

Background--The _v3 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 _v3 integrin expression in vivo.

Methods and Results--RP748, a novel ¹¹¹In-labeled _v3-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 _v3 at focal contacts. Activation of _v3 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 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 _v3 integrin and can track the injury-induced vascular proliferative process in vivo.

Key words: imaging • nuclear medicine • arteries • restenosis

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