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Quantitative measurement of lymphatic function in mice by noninvasive near-infrared imaging of a peripheral vein
Steven T. Proulx, … , Jean-Christophe Leroux, Michael Detmar
Steven T. Proulx, … , Jean-Christophe Leroux, Michael Detmar
Published January 12, 2017
Citation Information: JCI Insight. 2017;2(1):e90861. https://doi.org/10.1172/jci.insight.90861.
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Resource and Technical Advance Vascular biology

Quantitative measurement of lymphatic function in mice by noninvasive near-infrared imaging of a peripheral vein

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Abstract

Optical imaging methods have been developed to measure lymphatic function in skin; however, the lymphatic system of many organs is not accessible to this technology. Since lymphatic transport of macromolecules from any organ proceeds to the blood circulation, we aimed to develop a method that can measure lymphatic function by monitoring the fluorescence in a superficial vein of an interstitially injected tracer. We selected a 40-kDa PEGylated near-infrared dye conjugate, as it showed lymphatic system–specific uptake and extended circulation in blood. Lymphatic transport to blood from subcutaneous tissue required a transit time before signal enhancement was seen in blood followed by a steady rise in signal over time. Increased lymphatic transport was apparent in awake mice compared with those under continuous anesthesia. The methods were validated in K14-VEGFR-3-Fc and K14-VEGF-C transgenic mice with loss and gain of lymphatic function, respectively. Reduced lymphatic transport to blood was also found in aged mice. The technique was also able to measure lymphatic transport from the peritoneal cavity, a location not suitable for optical imaging. The method is a promising, simple approach for assessment of lymphatic function and for monitoring of therapeutic regimens in mouse models of disease and may have potential for clinical translation.

Authors

Steven T. Proulx, Qiaoli Ma, Diana Andina, Jean-Christophe Leroux, Michael Detmar

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Figure 1

Lymphatic specificity of potential imaging tracers.

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Lymphatic specificity of potential imaging tracers.
(A) Schematic showin...
(A) Schematic showing s.c. injection site on dorsal aspect of the paw and location of imaging region of interest (ROI) containing popliteal vein with adjoining collecting lymphatic vessels with mouse in prone position. (B) Representative video frames after s.c. injections of 2% Evans blue (20 μl), a 20-kDa PEG–IRDye680 conjugate (P20D680), and a 40-kDa PEG–IRDye680 conjugate (P40D680) (20 μl of 25 μM each). Uptake of Evans blue into popliteal vein (yellow arrowheads) as well as collecting lymphatic vessels was seen. P20D680 and P40D680 uptake was solely into collecting lymphatic vessels. Each image is representative of n = 3 mice per tracer. (C) Corresponding Prox1-GFP images of regions shown in B. Scale bars: 500 μm. (D) Schematic showing s.c. injection site on dorsal aspect of the paw and location of imaging ROI of the saphenous vein on the contralateral leg with mouse in supine position. (E) Representative video frames showing Evans blue signal in saphenous vein at t = 5 minutes after s.c. injection with no P20D680 or P40D680 signals in saphenous vein at the same time point. Scale bars: 500 μm. (F) Signal enhancement curve over time after s.c. injections of Evans blue, P20D680, and P40D680. n = 3 mice for each tracer. Dashed lines show SD.

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