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

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.

ELA-11 protects the heart against oxidative stress injury induced apoptosis through ERK/MAPK and PI3K/AKT signaling pathways

“…As an endogenous ligand of Apelin, APJ plays a cardiovascular protective role by binding to different G protein subtypes and trigger multiple signaling pathways, such as AMPK, PI3K/Akt or MAPK signaling pathways ( Li et al, 2021 ). Elabela was first identified as a novel ligand of APJ receptor in zebrafish embryos.…”

The Efficacy and Safety of the Shouzu Ning Decoction Treatment Versus Halometasone Plus Celecoxib Treatment in Patients With Grade 2 HFSR: A Randomized Clinical Trial

“… 12 - 14 Clinically, it has been used to treat peripheral vascular diseases, such as thromboangiitis obliterans, diabetic ulcers, and venous stasis ulcers. 15 - 18 The clinical characteristics of these diseases are similar to those of HFSR. Thus, SMYAD had been investigated in clinical setting to prevent HFSR in our previous research.…”

Clinical implications of inflammation in atheroma formation and novel therapies in cardiovascular diseases

“…Next, it may be relevant to highlight that the intima-media thickening mentioned earlier, along with the accumulation of pro-inflammatory factors and chemokines in the adventitia vascular layer, could induce oxygen deficiency which may trigger abnormal vasa vasorum neoangiogenesis within atherosclerotic lesions ( Li et al, 2021 ). On the other hand, solid malignancies have also been characterized by strongly enhanced angiogenesis within the tumour mass.…”

“…Finally, it has been noted that the abnormal vasa vasorum neo-angiogenesis within atherosclerotic plaque usually leads to the establishment of weak vessels prone to rupture and induce intra-plaque haemorrhages and instability. Thus, the inhibition of vasa vasorum neo-angiogenesis and/or the promotion of the correct maturation of newly formed intra-plaque vasculature could be an interesting therapeutic approach with the aim of reinforcing plaque stability ( Li et al, 2021 ).…”