Detection of injury-induced vascular remodeling by targeting activated alphavbeta3 integrin in vivo.
BACKGROUND
The alpha(v)beta3 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)beta3 integrin expression in vivo.


RESULTS
RP748, a novel 111In-labeled alpha(v)beta3-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)beta3 at focal contacts. Activation of alpha(v)beta3 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 beta3 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)beta3 integrin and can track the injury-induced vascular proliferative process in vivo.
Sadeghi
Mehran M
MM
Raymond and Beverly Sackler Cardiovascular Molecular Imaging Laboratory, Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, Conn, USA. mehran.sadeghi@yale.edu
Krassilnikova
Svetlana
S
Zhang
Jiasheng
J
Gharaei
Amir A
AA
Fassaei
Hooman Rastegar
HR
Esmailzadeh
Leila
L
Kooshkabadi
Ali
A
Edwards
Scott
S
Yalamanchili
Padmaja
P
Harris
Thomas D
TD
Sinusas
Albert J
AJ
Zaret
Barry L
BL
Bender
Jeffrey R
JR
D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D001157:Arterial Occlusive Diseases / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology; D002232:Carbocyanines / Q000378:metabolism / Q000493:pharmacokinetics*; D016893:Carotid Stenosis / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D005260:Female; D006573:Heterocyclic Compounds, 1-Ring / Q000378:metabolism / Q000493:pharmacokinetics*; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009942:Organometallic Compounds / Q000378:metabolism / Q000493:pharmacokinetics*; D011849:Radioactive Tracers; D013449:Sulfonamides / Q000378:metabolism; D015899:Tomography, Emission-Computed, Single-Photon
D001057:Apolipoproteins E; D002232:Carbocyanines; D006573:Heterocyclic Compounds, 1-Ring; D039302:Integrin alphaVbeta3; D009942:Organometallic Compounds; C494048:RP 748; D011849:Radioactive Tracers; D013449:Sulfonamides; C485703:TA 138; C494049:TA 145