Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.
Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.
Commun Biol. 2022 Sep 10;5(1):950. doi: 10.1038/s42003-022-03923-7.
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 β-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.
淋巴管生成是肿瘤转移、肥胖和移植物排斥等几种疾病的关键因素。淋巴管生成的内源性调节仅部分被理解。在这里，我们使用通常无血管的角膜作为模型，以鉴定淋巴管生成的内源性调节剂。对低淋巴管生成的 BALB/cN x 高淋巴管生成的 C57BL/6N 杂交的大群体进行数量性状基因座分析，并通过全转录组测序进行优先级排序，确定了一个负责染色体 17 上淋巴管结构差异的新基因，即胱硫醚 β-合酶（CBS）。在淋巴管内皮细胞中抑制 CBS 会导致增殖减少、迁移减少、管形成改变以及血管内皮生长因子受体 2 (VEGF-R2) 和 VEGF-R3 的表达减少，但 VEGF-C 和 VEGF-D 的配体不受影响。同样，在体内炎症诱导的淋巴管生成中，在 C57BL/6N 小鼠中用 CBS 的药理学抑制剂抑制后，明显减少。这些结果证实了 CBS 作为一种通过 VEGF 受体 2 和 3 调节作用的新型内源性淋巴管生成调节剂，并为与病理性淋巴管生成相关的疾病开辟了新的治疗途径。
