Search

Lymphatic vessels are lined by lymphatic endothelial cells (LECs), and are critical for health. However, the role of metabolism in lymphatic development has not yet been elucidated. Here we report that in transgenic mouse models, LEC-specific loss of CPT1A, a rate-controlling enzyme in fatty acid -oxidation, impairs lymphatic development. LECs use fatty acid -oxidation to proliferate and for epigenetic regulation of lymphatic marker expression during LEC differentiation. Mechanistically, the transcription factor PROX1 upregulates CPT1A expression, which increases acetyl coenzyme A production dependent on fatty acid -oxidation. Acetyl coenzyme A is used by the histone acetyltransferase p300 to acetylate histones at lymphangiogenic genes. PROX1p300 interaction facilitates preferential histone acetylation at PROX1-target genes. Through this metabolism-dependent mechanism, PROX1 mediates epigenetic changes that promote lymphangiogenesis. Notably, blockade of CPT1 enzymes inhibits injury-induced lymphangiogenesis, and replenishing acetyl coenzyme A by supplementing acetate rescues this process in vivo., Author(s): Brian W. Wong [1, 2]; Xingwu Wang [1, 2]; Annalisa Zecchin [1, 2]; Bernard Thienpont [3, 4]; Ivo Cornelissen [1, 2]; Joanna Kalucka [1, 2]; Melissa Garca-Caballero [5]; Rindert [...]

Hypoxia-inducible factor (HIF)-1-alpha deficiency prevents cells from undergoing hypoxic growth arrest, and, in a mitogenic microenvironment, stimulates proliferation. It has been established that tumour vascularization is largely controlled by HIF-1-alpha, partly as a result of upregulation of vascular endothelial growth factor. The HIF-1-alpha-dependent growth arrest in response to hypoxia has similarities with the p53-mediated control of growth arrest/apoptosis in response to genotoxic or physical stresses.

Genetic research shows that mice born without factor VII (FVII) binding capabilities develop without deformity but die of fatal perinatal haemorrhaging from normal blood vessels. Evidence suggests that tissue factor-FVII-/-initiated fibrin formation is not critical to embryonic development but is involved in other embryonic development processes.

Embryos containing a single inactive vascular endothelial growth factor (VEGF) gene show abnormal development of blood vessels. The homozygous VEGF-deficient embryos exhibit more abnormality in the blood vessel development, and more fatality than heterozygous mutants. The haploid-insufficient phenotype is associated with heterozygous VEGF deficiency. VEGF participation in vascular development depends on the ligand dose. The embryonic phenotypes from germline transmission and aggregation of heterozygous mutant embryo stem cells with tetraploid hosts are similar.