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 11 isoform of soluble guanylate cyclase (sGC), that vascular endothelial growth factor-A potently induces sGC11, and that nitric oxide (NO) -induced LEC proliferation, migration, and cGMP production in LECs are specifically dependent on sGC11. 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/sGC11/cGMP pathway in modulating lymphatic vessel function. The blockade of sGC11 signaling might serve as a novel therapeutic strategy for inhibiting lymphangiogenesis and inflammation, in addition to its effects on the blood vasculature.—Kajiya, K., Huggenberger, R., Drinnenberg, I., Ma, B., and Detmar, M. Nitric oxide mediates lymphatic vessel activation via soluble guanylate cyclase 11-impact on inflammation.