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.


APPROACH AND 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.
['Cui|Jie|J|', 'Kessinger|Chase W|CW|', 'McCarthy|Jason R|JR|', 'Sosnovik|David E|DE|', 'Libby|Peter|P|', 'Thadhani|Ravi I|RI|', 'Jaffer|Farouc A|FA|']
D000818:Animals D001164:Arteriovenous Fistula D001783:Blood Flow Velocity D002199:Capillary Permeability D002339:Carotid Arteries D049109:Cell Proliferation D003251:Constriction, Pathologic D003911:Dextrans D004195:Disease Models, Animal D004730:Endothelium, Vascular D005456:Fluorescent Dyes D006965:Hyperplasia D007601:Jugular Veins 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
endothelium stenosis arteriovenous fistula imaging