Notoginsenoside R 1 decreases intraplaque neovascularization by governing pericyte-endothelial cell communication via Ang1/Tie2 axis in atherosclerosis.

Atherosclerosis represents the major cause of mortality worldwide and triggers higher risk of acute cardiovascular events. Pericytes-endothelial cells (ECs) communication is orchestrated by ligand-receptor interaction generating a microenvironment which results in intraplaque neovascularization, that is closely associated with atherosclerotic plaque instability. Notoginsenoside R 1 (R 1 ) exhibits anti-atherosclerotic bioactivity, but its effect on angiogenesis in atherosclerotic plaque remains elusive. The aim of our study is to explore the therapeutic effect of R 1 on vulnerable plaque and investigate its potential mechanism against intraplaque neovascularization. The impacts of R 1 on plaque stability and intraplaque neovascularization were assessed in ApoE -/- mice induced by high-fat diet. Pericytes-ECs direct or non-direct contact co-cultured with VEGF-A stimulation were used as the in vitro angiogenesis models. Overexpressing Ang1 in pericytes was performed to investigate the underlying mechanism. In vivo experiments, R 1 treatment reversed atherosclerotic plaque vulnerability and decreased the presence of neovessels in ApoE -/- mice. Additionally, R 1 reduced the expression of Ang1 in pericytes. In vitro experiments demonstrated that R 1 suppressed pro-angiogenic behavior of ECs induced by pericytes cultured with VEGF-A. Mechanistic studies revealed that the anti-angiogenic effect of R 1 was dependent on the inhibition of Ang1 and Tie2 expression, as the effects were partially reversed after Ang1 overexpressing in pericytes. Our study demonstrated that R 1 treatment inhibited intraplaque neovascularization by governing pericyte-EC association via suppressing Ang1-Tie2/PI3K-AKT paracrine signaling pathway. R 1 represents a novel therapeutic strategy for atherosclerotic vulnerable plaques in clinical application.