Nitric oxide mediates lymphatic vessel activation via soluble guanylate cyclase alpha1beta1-impact on inflammation.
The lymphatic vascular system regulates tissue fluid homeostasis and the afferent phase of the immune response, and it is also involved in tumor metastasis. There is increasing evidence that lymphatic vessels also mediate acute and chronic inflammation. However, the mechanisms and functional consequences of lymphangiogenesis under inflammatory conditions are largely unknown. Here, we show that lymphatic endothelial cells (LECs) specifically express the alpha1beta1 isoform of soluble guanylate cyclase (sGC), that vascular endothelial growth factor-A potently induces sGCalpha1beta1, and that nitric oxide (NO) -induced LEC proliferation, migration, and cGMP production in LECs are specifically dependent on sGCalpha1beta1. Moreover, the specific sGC inhibitor NS-2028 completely prevents ultraviolet B-irradiation-induced lymphatic vessel enlargement, edema formation, and skin inflammation in vivo. These findings identify a crucial role of the NO/sGCalpha1beta1/cGMP pathway in modulating lymphatic vessel function. The blockade of sGCalpha1beta1 signaling might serve as a novel therapeutic strategy for inhibiting lymphangiogenesis and inflammation, in addition to its effects on the blood vasculature.
Kajiya
Kentaro
K
Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology Zurich, Wolfgang-Pauli-Str. 10, HCI H303, CH-8093 Zurich, Switzerland.
Huggenberger
Reto
R
Drinnenberg
Ines
I
Ma
Beijia
B
Detmar
Michael
M
D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000096:biosynthesis; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007111:Immunity, Cellular / Q000276:immunology; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D042601:Lymphatic Vessels / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010069:Oxadiazoles / Q000494:pharmacology; D010078:Oxazines / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D026423:S-Nitroso-N-Acetylpenicillamine / Q000378:metabolism; D000071756:Soluble Guanylyl Cyclase
D004791:Enzyme Inhibitors; C111257:NS 2028; D010069:Oxadiazoles; D010078:Oxazines; D018160:Receptors, Cytoplasmic and Nuclear; D009569:Nitric Oxide; D026423:S-Nitroso-N-Acetylpenicillamine; D052250:Nitric Oxide Synthase Type III; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP