Nitric oxide permits hypoxia-induced lymphatic perfusion by controlling arterial-lymphatic conduits in zebrafish and glass catfish
- Lasse Dahl Ejby Jensena,
- Renhai Caoa,
- Eva-Maria Hedlunda,
- Iris Söllb,
- Jon O. Lundbergc,
- Giselbert Hauptmannb,
- John Fleng Steffensend and
- Yihai Caoa,1
- Departments of aMicrobiology, Tumor and Cell Biology and
- cPhysiology and Pharmacology, Karolinska Institute, SE-171 77 Stockholm, Sweden;
- bDepartment of Life Sciences, Södertörn University and BioNut, Karolinska Institute, Huddinge, Sweden; and
- dMarine Biological Laboratory, University of Copenhagen, Strandpromenaden 5, Helsingor, DK-3000, Denmark
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Edited by Robert Langer, Massachusetts Institute of Technology, Cambridge, MA, and approved September 4, 2009 (received for review July 9, 2009)
Abstract
The blood and lymphatic vasculatures are structurally and functionally coupled in controlling tissue perfusion, extracellular interstitial fluids, and immune surveillance. Little is known, however, about the molecular mechanisms that underlie the regulation of bloodlymphatic vessel connections and lymphatic perfusion. Here we show in the adult zebrafish and glass catfish (Kryptopterus bicirrhis) that blood-lymphatic conduits directly connect arterial vessels to the lymphatic system. Under hypoxic conditions, arterial-lymphatic conduits (ALCs) became highly dilated and linearized by NO-induced vascular relaxation, which led to blood perfusion into the lymphatic system. NO blockage almost completely abrogated hypoxia-induced ALC relaxation and lymphatic perfusion. These findings uncover mechanisms underlying hypoxia-induced oxygen compensation by perfusion of existing lymphatics in fish. Our results might also imply that the hypoxia-induced NO pathway contributes to development of progression of pathologies, including promotion of lymphatic metastasis by modulating arterial-lymphatic conduits, in the mammalian system.
Footnotes
- 1To whom correspondence should be addressed. E-mail: yihai.cao{at}mtc.ki.se
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Author contributions: L.D.E.J., R.C., J.O.L., J.F.S., and Y.C. designed research; L.D.E.J. and R.C. performed research; E.-M.H., I.S., J.O.L., G.H., J.F.S., and Y.C. contributed new reagents/analytic tools; L.D.E.J., R.C., J.F.S., and Y.C. analyzed data; and L.D.E.J., J.F.S., and Y.C. wrote the paper.
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The authors declare no conflict of interest.
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This article is a PNAS Direct Submission.
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This article contains supporting information online at www.pnas.org/cgi/content/full/0907608106/DCSupplemental.
