Cystathionine β-synthase as novel endogenous regulator of lymphangiogenesis via modulating VEGF receptor 2 and 3.
Niloofar HatamiChristian BüttnerFelix BockSara SimforsGwen MusialAndré ReisClaus CursiefenThomas ClahsenPublished in: Communications biology (2022)
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.
Keyphrases
- vascular endothelial growth factor
- endothelial cells
- high glucose
- transcription factor
- genome wide
- type diabetes
- single cell
- poor prognosis
- signaling pathway
- oxidative stress
- lymph node
- high resolution
- metabolic syndrome
- squamous cell carcinoma
- binding protein
- long non coding rna
- weight loss
- dna methylation
- smoking cessation
- drug induced
- skeletal muscle
- rna seq
- adipose tissue
- replacement therapy
- rectal cancer
- stress induced