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(Circulation Research. 2004;95:204.)
© 2004 American Heart Association, Inc.

Integrative Physiology

Endothelial Nitric Oxide Synthase Regulates Microlymphatic Flow via Collecting Lymphatics

Jeroen Hagendoorn, Timothy P. Padera, Satoshi Kashiwagi, Naohide Isaka, Fatima Noda, Michelle I. Lin, Paul L. Huang, William C. Sessa, Dai Fukumura, Rakesh K. Jain

From the Department of Radiation Oncology (J.H., T.P.P., S.K., N.I., D.F., R.K.J.), E.L. Steele Laboratory for Tumor Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Mass; Division of Cardiology (F.N., P.L.H.), Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Mass; and the Department of Pharmacology (M.I.L., W.C.S.), Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, Conn.

Correspondence to Rakesh K. Jain, E.L. Steele Laboratory for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, 100 Blossom St, Cox 7, Boston, MA 02114. E-mail jain{at}steele.mgh.harvard.edu

Functional interactions between the initial and collecting lymphatics, as well as the molecular players involved, remain elusive. In this study, we assessed the influence of nitric oxide (NO) on lymphatic fluid velocity and flow, using a mouse tail model that permits intravital microscopy and microlymphangiography. We found that NO synthase (NOS) inhibition decreased lymphatic fluid velocity in the initial lymphatics, without any effect on their morphology. Using the same model, we found a similar effect in eNOS^–/– mice and in mice treated with a selective endothelial NOS (eNOS) inhibitor. Next, we uncoupled the superficial initial lymphatics from the deeper collecting lymphatics by ligating the latter and found that lymphatic fluid velocity in NOS-inhibited mice became equal to that in control animals. Surprisingly, lymphatic fluid velocity was significantly increased after ligating the collecting lymphatics, and there was a concomitant increase in injection rate and mean lymphatic vessel diameter. Our results provide the first in vivo evidence that eNOS affects function of the whole microlymphatic system and that it is regulated via the collecting lymphatics.

Key Words: microlymphatics • eNOS • lymphatic function • edema • lymphangiography

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