In vivo nanoparticle assessment of pathological endothelium predicts the development of inflow stenosis in murine arteriovenous fistula.
OBJECTIVE
In vivo assessment of pathological endothelium within arteriovenous fistula (AVF) could provide new insights into inflow stenosis, a common cause of AVF primary failure in end-stage renal disease patients. Here we developed nanoparticle-based imaging strategies to assess pathological endothelium in vivo and elucidate its relationship to neointimal hyperplasia formation in AVF.


RESULTS
Jugular-carotid AVFs were created in C57BL/6 mice (n=38). Pathological endothelium in the AVF was visualized and quantified in vivo using dextranated magnetofluorescent nanoparticles (CLIO-VT680 [cross-linked iron oxide-VivoTag680]). At day 14, CLIO-VT680 was deposited in AVF, but only minimally in sham-operated arteries. Transmission electron microscopy revealed that CLIO-VT680 resided within endothelial cells and in the intimal extracellular space. Endothelial cells of AVF, but not control arteries, expressed vascular cell adhesion molecule-1 and showed augmented endothelial permeability near the anastomosis. Intravital microscopy demonstrated that CLIO-VT680 deposited most intensely near the AVF anastomosis (P<0.0001). The day 14 intravital microscopy CLIO-VT680 signal predicted the subsequent site and magnitude of AVF neointimal hyperplasia at day 42 (r=0.58, P<0.05). CLIO-VT680 deposition in AVF was further visualized by ex vivo MRI.


CONCLUSIONS
AVF develop a pathological endothelial response that can be assessed in vivo via nanoparticle-enhanced imaging. AVF endothelium is activated and exhibits augmented permeability, offering a targeting mechanism for nanoparticle deposition and retention in pathological endothelium. The in vivo AVF nanoparticle signal identified and predicted subsequent inflow neointimal hyperplasia. This approach could be used to test therapeutic interventions aiming to restore endothelial health and to decrease early AVF failure caused by inflow stenosis.
From the Cardiovascular Research Center (J.C., C.W.K., D.E.S., F.A.J.), Division of Cardiology (P.L.), Division of Nephrology (J.C., R.I.T.), Center for System Biology (J.R.M.), Martinos Center for Biomedical Imaging (D.E.S.), and Wellman Center for Photomedicine (F.A.J.), Massachusetts General Hospital, Boston.
Jie
J
Cui
From the Cardiovascular Research Center (J.C., C.W.K., D.E.S., F.A.J.), Division of Cardiology (P.L.), Division of Nephrology (J.C., R.I.T.), Center for System Biology (J.R.M.), Martinos Center for Biomedical Imaging (D.E.S.), and Wellman Center for Photomedicine (F.A.J.), Massachusetts General Hospital, Boston.
Chase W
CW
Kessinger
From the Cardiovascular Research Center (J.C., C.W.K., D.E.S., F.A.J.), Division of Cardiology (P.L.), Division of Nephrology (J.C., R.I.T.), Center for System Biology (J.R.M.), Martinos Center for Biomedical Imaging (D.E.S.), and Wellman Center for Photomedicine (F.A.J.), Massachusetts General Hospital, Boston.
Jason R
JR
McCarthy
From the Cardiovascular Research Center (J.C., C.W.K., D.E.S., F.A.J.), Division of Cardiology (P.L.), Division of Nephrology (J.C., R.I.T.), Center for System Biology (J.R.M.), Martinos Center for Biomedical Imaging (D.E.S.), and Wellman Center for Photomedicine (F.A.J.), Massachusetts General Hospital, Boston.
David E
DE
Sosnovik
From the Cardiovascular Research Center (J.C., C.W.K., D.E.S., F.A.J.), Division of Cardiology (P.L.), Division of Nephrology (J.C., R.I.T.), Center for System Biology (J.R.M.), Martinos Center for Biomedical Imaging (D.E.S.), and Wellman Center for Photomedicine (F.A.J.), Massachusetts General Hospital, Boston.
Peter
P
Libby
From the Cardiovascular Research Center (J.C., C.W.K., D.E.S., F.A.J.), Division of Cardiology (P.L.), Division of Nephrology (J.C., R.I.T.), Center for System Biology (J.R.M.), Martinos Center for Biomedical Imaging (D.E.S.), and Wellman Center for Photomedicine (F.A.J.), Massachusetts General Hospital, Boston.
Ravi I
RI
Thadhani
From the Cardiovascular Research Center (J.C., C.W.K., D.E.S., F.A.J.), Division of Cardiology (P.L.), Division of Nephrology (J.C., R.I.T.), Center for System Biology (J.R.M.), Martinos Center for Biomedical Imaging (D.E.S.), and Wellman Center for Photomedicine (F.A.J.), Massachusetts General Hospital, Boston. fjaffer@mgh.harvard.edu.
Farouc A
FA
Jaffer
D000818:Animals; D001164:Arteriovenous Fistula / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D001783:Blood Flow Velocity; D002199:Capillary Permeability; D002339:Carotid Arteries / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology / Q000601:surgery / Q000648:ultrastructure; D049109:Cell Proliferation; D003251:Constriction, Pathologic; D003911:Dextrans; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology / Q000601:surgery / Q000648:ultrastructure; D005456:Fluorescent Dyes; D006965:Hyperplasia; D007601:Jugular Veins / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology / Q000601:surgery / Q000648:ultrastructure; D008279:Magnetic Resonance Imaging; D058185:Magnetite Nanoparticles; D008297:Male; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D008856:Microscopy, Fluorescence; D058426:Neointima; D011237:Predictive Value of Tests; D012039:Regional Blood Flow; D013997:Time Factors; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D003911:Dextrans; D005456:Fluorescent Dyes; D058185:Magnetite Nanoparticles; D019010:Vascular Cell Adhesion Molecule-1
arteriovenous fistula; endothelium; imaging; stenosis