Downregulation of low-density lipoprotein receptor mRNA in lymphatic endothelial cells impairs lymphatic function through changes in intracellular lipids.

Impairment in lymphatic transport is associated with the onset and progression of atherosclerosis in animal models. The downregulation of low-density-lipoprotein receptor (LDLR) expression, rather than increased circulating cholesterol level , is involved in early atherosclerosis-related lymphatic dysfunction. Enhancing lymphatic function in mice with a mutant form of VEGF-C (VEGF-C 152s), a selective VEGFR-3 agonist, successfully delayed atherosclerotic plaque onset when mice were subsequently fed a high-fat diet.

Early rescue of lymphatic function limits atherosclerosis progression in Ldlr mice.

Background And Aims: Our previous data showed that lymphatic function impairment occurs before the onset of atherosclerosis in mice and is precociously associated with a defect in the propelling capacity of the collecting lymphatic vessels. Concomitantly, we found that lymphatic transport can be restored in mice by systemic injections of a mutant form of VEGF-C (VEGF-C 152s), a growth factor known to increase mesenteric collecting lymphatic vessel pumping through a VEGFR-3-dependent mechanism in rats. In the present study, we aimed to determine whether and how early modulation of collecting lymphatic vessel function could restrain atherosclerosis onset and limit its progression.