VASCULAR BIOLOGY An important role of lymphatic vessel activation in limiting acute inflammation

In contrast to the established role of blood vessel remodeling in inflammation, the biologic function of the lymphatic vasculature in acute inflammation has remained less explored. We studied 2 es-tablished models of acute cutaneous in-flammation, namely, oxazolone-induced delayed-type hypersensitivity reactions and ultraviolet B irradiation, in keratin 14-vascular endothelial growth factor (VEGF)-C and keratin 14-VEGF-D trans-genic mice. These mice have an ex-panded network of cutaneous lymphatic vessels. Transgenic delivery of the lymph-angiogenic factors VEGF-C and the VEGFR-3 specific ligand mouse VEGF-D significantly limited acute skin inflamma-tion in both experimental models, with a strong reduction of dermal edema. Ex-pression of VEGFR-3 by lymphatic endo-thelium was strongly down-regulated at the mRNA and protein level in acutely inflamed skin, and no VEGFR-3 expres-sion was detectable on inflamed blood vessels and dermal macrophages. There was no major change of the inflammatory cell infiltrate or the composition of the inflammatory cytokine milieu in the in-flamed skin of VEGF-C or VEGF-D trans-genic mice. However, the increased net-work of lymphatic vessels in these mice significantly enhanced lymphatic drain-age from the ear skin. These results pro-vide evidence that specific lymphatic vessel activation limits acute skin inflam-mation via promotion of lymph flow from the skin and reduction of edema forma-tion. (Blood. 2011;117(17):4667-4678