Alphavbeta3-targeted detection of arteriopathy in transplanted human coronary arteries: an autoradiographic study.
Graft arteriopathy (GA), characterized by diffuse concentric narrowing of coronary arteries, is the major cause of late graft failure in cardiac transplantation. alphavbeta3 Integrin is up-regulated in proliferating vascular cells and may constitute an appropriate target for imaging GA. We used a human/mouse chimeric model of GA, in which segments of human coronary artery were transplanted to severe combined immunodeficiency mice, followed by reconstitution with allogeneic human peripheral blood mononuclear cells (PBMC). This led to vascular remodeling characterized by neointima formation over a period of 4 wk. alphavbeta3 expression in the graft was minimal in animals without PBMC, considerably increased by 2 wk, and decreased toward baseline by 4 wk after PBMC reconstitution. Cell proliferation was maximal at 2 wk, correlating with peak alphavbeta3 expression. RP748, an 111In-labeled alphavbeta3 (active conformation)-targeted radiotracer was injected into groups of 5 recipients at 0, 2, and 4 wk after PBMC reconstitution. Relative uptakes, defined as autoradiographic intensity in the graft/native aortas closely tracked the proliferative process. Specificity of uptake was demonstrated using excess nonlabeled tracer. In conclusion, alphavbeta3 integrin is transiently up-regulated (and activated) in GA and may be targeted by RP748 for detection of the proliferative process in early GA.
Zhang
Jiasheng
J
Raymond and Beverly Sackler Cardiovascular Molecular Imaging Laboratory, Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
Krassilnikova
Svetlana
S
Gharaei
Amir A
AA
Fassaei
Hooman Rastegar
HR
Esmailzadeh
Leila
L
Asadi
Abolfazl
A
Edwards
D Scott
DS
Harris
Thomas D
TD
Azure
Michael
M
Tellides
George
G
Sinusas
Albert J
AJ
Zaret
Barry L
BL
Bender
Jeffrey R
JR
Sadeghi
Mehran M
MM
D000818:Animals; D001011:Aorta / Q000473:pathology; D001345:Autoradiography / Q000379:methods*; D002340:Carotid Artery Diseases / Q000473:pathology / Q000628:therapy; D002465:Cell Movement; D049109:Cell Proliferation; D017690:Cell Transplantation; D002478:Cells, Cultured; D002678:Chimera; D003331:Coronary Vessels / Q000473:pathology* / Q000637:transplantation*; D003720:Densitometry; D004730:Endothelium, Vascular / Q000166:cytology; D016027:Heart Transplantation; D006573:Heterocyclic Compounds, 1-Ring / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D039302:Integrin alphaVbeta3 / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D019394:Ki-67 Antigen / Q000096:biosynthesis; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D008856:Microscopy, Fluorescence; D009942:Organometallic Compounds / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D013997:Time Factors; D016378:Tissue Transplantation / Q000379:methods*; D015854:Up-Regulation; D014652:Vascular Diseases / Q000473:pathology
D006573:Heterocyclic Compounds, 1-Ring; D039302:Integrin alphaVbeta3; D019394:Ki-67 Antigen; D009942:Organometallic Compounds; C494048:RP 748; D011993:Recombinant Fusion Proteins