The Nitric Oxide Receptor Soluble Guanylyl Cyclase Is Found in Lymphatic Vessels of Arthritic Mice and Inhibition Alters Lymphatic Pulse

Homaira Rahimi¹, Yawen Ju², Echoe M. Bouta³, Ronald Wood⁴, Christopher T. Ritchlin⁵ and Edward M. Schwarz⁶, ¹Rheumatology, University of Rochester/Golisano Children's Hospit, Rochester, NY, ²Univ of Rochester Med Ctr, University of Rochester, Rochester, NY, ³University of Rochester School of Medicine and Dentistry, Rochester, NY, ⁴Department of Urology, University of Rochester Medical Center, Rochester, NY, ⁵Allergy Immunology & Rheumatology, University of Rochester Medical Center, Rochester, NY, ⁶Center for Musculoskeletal Research, University of Rochester, Rochester, NY

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: Animal models, Cell Signaling, Knee, Lymph node, rheumatic disease and rheumatoid arthritis

Session Information

Session Title: Rheumatoid Arthritis - Animal Models

Session Type: Abstract Submissions (ACR)

Background/Purpose: Rheumatoid arthritis (RA) is a chronic erosive inflammatory condition that is characterized by episodes of “flare” due to synovitis of an affected joint. It has been shown in the tumor necrosis factor transgenic (TNF-Tg) mouse model of RA that the popliteal lymph node (PLN) can serve as a biomarker of arthritic flare. Prior to onset of knee flare, the PLN is expanded and an intrinsic lymphatic pulse is maintained. However, at some point following chronic ankle arthritis, the PLN suddenly collapses, the lymphatic pulse is lost, and knee arthritis occurs. Here, we show that the nitric oxide (NO) signaling pathway, known to be involved in blood vasculature contractility, is involved in lymphatic vessel contractility, and that the NO receptor soluble guanylyl cyclase (sGC) may be a key regulator. Methods: Immunofluorescent microscopy was performed on fresh frozen histology sections of PLN from wild type (WT) and TNF-Tg mice stained for alpha (a1, a2) and beta (b1) subunits of sGC and co-localized with smooth muscle actin. In WT mice, near infrared indocyanine green (NIR-ICG) imaging was performed to determine and quantify lymphatic pulse. The sGC inhibitor NS2028 or control vehicle was injected into the footpads of mice, and lymphatic pulse was measured with NIR-ICG imaging 30 minutes later. Results: Immunohistochemistry confirmed the presence of all sGC subunits in PLN from both WT and TNF-Tg mice. Of the six footpads injected with sGC inhibitor NS2028, a clear alteration in the lymphatic pulse with more frequent doublet and triplet spikes compared to control was observed (Figure 1). Quantification of the pulse showed an increased lymphatic pulse in the drug treated limb compared to control (2.66 vs 1.39 pulse per minute, respectively, p<0.05). Conclusion: The presence of sGC receptor subunits in the lymphatic tissue of WT and TNF-Tg mice strongly supports a role for nitric oxide signaling in lymphatic contractility. Furthermore, local injection of sGC inhibitor in WT mice results in a dysregulated lymphatic pulse with an increased rate. This novel finding of increased lymphatic pulse rate with sGC inhibition suggests resumption of the lymphatic pulse in arthritic flare in mice via specific targeting of the sGC receptor may ameliorate flare in inflammatory arthritis.

Figure 1.

Disclosure:

H. Rahimi,
None;

Y. Ju,
None;

E. M. Bouta,
None;

R. Wood,
None;

C. T. Ritchlin,
None;

E. M. Schwarz,
None.

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