Cystathionine β-synthase as novel endogenous regulator of lymphangiogenesis via modulating VEGF receptor 2 and 3

Lymphangiogenesis is a key player in several diseases such as tumor metastasis, obesity, and graft rejection. Endogenous regulation of lymphangiogenesis is only partly understood. Here we use the normally avascular cornea as a model to identify endogenous regulators of lymphangiogenesis. Quantitative trait locus analysis of a large low-lymphangiogenic BALB/cN x high-lymphangiogenic C57BL/6 N intercross and prioritization by whole-transcriptome sequencing identify a novel gene responsible for differences in lymphatic vessel architecture on chromosome 17, the cystathionine beta-synthase (Cbs). Inhibition of CBS in lymphatic endothelial cells results in reduce proliferation, migration, altered tube-formation, and decrease expression of vascular endothelial growth factor (VEGF) receptor 2 (VEGF-R2) and VEGF-R3, but not their ligands VEGF-C and VEGF-D. Also in vivo inflammation-induced lymphangiogenesis is significantly reduce in C57BL/6 N mice after pharmacological inhibition of CBS. The results confirm CBS as a novel endogenous regulator of lymphangiogenesis acting via VEGF receptor 2 and 3-regulation and open new treatment avenues in diseases associated with pathologic lymphangiogenesis. Quantitative trait locus analysis of BALB/cN x C57BL/6 N intercross identifies cystathionine beta-synthase as a previously unknown regulator of lymphangiogenesis by affecting VEGF-R2/VEGF-R3 expression in lymphatic endothelial cells.