To investigate the effect of vascular endothelial growth factor-C (VEGFC)/vascular endothelial growth factor receptor-3 (VEGFR3) pathway on the regulation of lymphangiogenesis on the occurrence of atherosclerosis (AS), and to reveal the intervention mechanism of Linggui Zhugan Decoction (苓桂术甘汤).

ApoE^-/-mice fed with high-fat diet were fed to construct an AS model, and C57BL/6J mice were used as the blank groups, which were blank control group, model group, Linggui Zhugan Decoction low, medium and high dose groups. The blood lipid levels of mice in each group were checked by automatic bioanalyzer, and the pathological changes of the mouse aorta were observed by HE staining, and the mRNA and protein levels of lymphatic vessel endothelial receptor-1 (LYVE-1), VEGFR3, vascular endothelial growth factor-D (VEGFD), vascular endothelial growth factor receptor-2 (VEGFR2), podoplanin (PDPN), protein kinase B (AKT), extracellular signal-regulated kinase 1/2 (ERK1/2) and VEGFC were detected by qRT-PCR and Western blot.

Compared with those of the control group, the serum levels of triglyceride (TG), total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) in the model group were significantly increased (P<0.01), the structure of the aorta was abnormal, the large atheroma plaques were seen. The expressions of genes and proteins of LYVE-1, VEGFD, VEGFR2, PDPN, VEGFR3 and VEGFC in the aorta were significantly decreased (P<0.05 or P<0.01), and the protein expressions of AKT and ERK1/2 were significantly decreased (P<0.01). After the intervention of Linggui Zhugan Decoction, dyslipidemia was improved, the structure of the aortic wall was reduced, the atheroma plaque was reduced, the expressions of genes and proteins of LYVE-1, VEGFD, VEGFR2 and VEGFC in arteries were significantly increased (P<0.05 or P<0.01), the protein expressions of AKT and ERK1/2 in the aorta were significantly increased (P<0.05 or P<0.01) and the protein expressions of PDPN and VEGFR3 genes in the aortic of Linggui Zhugan Decoction medium and high dose groups were significantly increased (P<0.05 or P<0.01). Among them, the improvement of Linggui Zhugan Decoction high dose group was more obvious.

Linggui Zhugan Decoction may promote lymphangiogenesis by affecting the VEGFC/VEGF3 pathway and participate in the regulation of the occurrence and development of AS.