Effect and Mechanism of Si-Miao-Yong-An on Vasa Vasorum Remodeling in ApoE-/- Mice with Atherosclerosis Vulnerable Plague.

Meng Li,Yueyao Wang,Ke Zhu,Zhongwen Qi,Junping Zhang

doi:10.3389/fphar.2021.634611

Abstract

Objective: To observe the effect of Si-Miao-Yong-An (SMYA) on atherosclerosis (AS) vulnerable plaques, and to further explore the mechanism by vasa vasorum (VV) angiogenesis and maturation as an entry point. Methods: SPF-class healthy male ApoE−/− mice were randomized into model group, simvastatin group and SMYA group, and C57BL/6 mice were used as the control group. After 8 weeks of intervention, the pathological morphology of plaque was observed by HE staining; the VV density in plaque and aortic adventitia were observed by immunohistochemistry; VV maturation was measured by double-labelling immunofluorescence; the critical proteins of HIF-1α-Apelin/APJ and Ang-1/Tie signal pathways were detected by western blotting. Results: SMYA decreased the plaque area and the ratio of plaque to lumen area; increased the minimum thickness of fibrous cap and its effect was greater than simvastatin. SMYA suppressed the VV neovascularization; promoted smooth muscle cells recruitment and VV maturation, which maintained plaque stability; its effect was obviously superior to simvastatin. SMYA deceased the expression of HIF-1α, Apelin, APJ, Phospho-MEK1/2 (Ser217/221), Phospho-p44/42 MAPK (Erk1/2) (Thr202/Tyr204), Phospho-p70 S6 Kinase (Thr421/Ser424), Ang-2 and Tie-2; it also increased the expression of Ang-1, Phospho-Akt (Ser473), Phospho-FOXO1 (Ser256) and Survivin. Conclusions: SMYA can decrease the AS plaque area in ApoE−/− mice, suppress the VV neovascularization and promote the VV maturation, and stabilize AS vulnerable plaque. The mechanism could be regulating the HIF-1α-Apelin/APJ and Ang-1/Tie signal pathways.

Highlights

In recent years, the research on AS has gradually changed from the “inside-out”—inflammatory response mechanism focusing on the endangium to “outside-in” (Ruan et al, 2013; Fatkhullina et al, 2016)
VV neovascularization in plaques is a critical factor to promote the stable plaques changing into vulnerable plaques, which is closely related to the occurrence of intra-plaque hemorrhage, plaque rupture and clinical cardiovascular and cerebrovascular events (Li et al, 2017)
Only scattered red atherosclerotic plaques could be seen and the plaque area of aorta intima was significantly decreased in simvastatin group (p < 0.01); a small amount of red atherosclerotic plaques was observed and the plaque area of aorta intima was significantly decreased in SMYA group (p < 0.05) (Figure 1)

Summary

Introduction

The research on AS has gradually changed from the “inside-out”—inflammatory response mechanism focusing on the endangium to “outside-in” (Ruan et al, 2013; Fatkhullina et al, 2016). Another study observed the coronary arteries of hyperlipidemia pigs and found abnormal hyperplasia and increased density of adventitia VV at the early stage of AS, and the VV density was positively correlated with the degree of AS lesions (Gössl et al, 2003). The pathologic neovascularization has structural defects, with great brittleness, high leakage and being easy to rupture and bleed. Instability and vulnerability of plaques cause the major clinical risks of AS lesions (Xu et al, 2015). VV neovascularization in plaques is a critical factor to promote the stable plaques changing into vulnerable plaques, which is closely related to the occurrence of intra-plaque hemorrhage, plaque rupture and clinical cardiovascular and cerebrovascular events (Li et al, 2017)

Methods

Results

Conclusion