Objective

Statins pleiotropically provide additional benefits in reducing atherosclerosis, but their effects on intraplaque angiogenesis (IPA) and hemorrhage (IPH) remain unclear. Therefore, we discriminated statin’s lipid-lowering dependent and independent effects on IPA and IPH.

Approach and results

ApoE3*Leiden mice are statin-responsive due to ApoE and LDLR presence, but also allow to titrate plasma cholesterol levels by diet. Therefore, ApoE3*Leiden mice were fed a high-cholesterol-inducing-diet (HCD) with or without atorvastatin (A) or a moderate-cholesterol-inducing-diet (MCD). Mice underwent vein graft surgery to induce lesions with IPA and IPH. Cholesterol levels were significantly reduced in MCD (56%) and HCD + A (39%) compared to HCD with no significant differences between MCD and HCD + A. Both MCD and HCD + A have a similar reduction in vessel remodeling and inflammation comparing to HCD. IPA was significantly decreased by 30% in HCD + A compared to HCD or MCD. Atorvastatin treatment reduced the presence of immature vessels by 34% vs. HCD and by 25% vs. MCD, resulting in a significant reduction of IPH. Atorvastatin’s anti-angiogenic capacity was further illustrated by a dose-dependent reduction of ECs proliferation and migration. Cultured mouse aortic-segments lost sprouting capacity upon atorvastatin treatment and became 30% richer in VE-Cadherin expression and pericyte coverage. Moreover, Atorvastatin inhibited ANGPT2 release and decreased VE-Cadherin(Y685)-phosphorylation in ECs.

Conclusions

Atorvastatin has beneficial effects on vessel remodeling due to its lipid-lowering capacity. Atorvastatin has strong pleiotropic effects on IPA by decreasing the number of neovessels and on IPH by increasing vessel maturation. Atorvastatin improves vessel maturation by inhibiting ANGPT2 release and phospho(Y658)-mediated VE-Cadherin internalization.

中文翻译：

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阿托伐他汀通过抑制 ANGPT2 释放和 VE-Cadherin 内化来多效性减少斑块内血管生成和斑块内出血

客观的

他汀类药物在减少动脉粥样硬化方面具有多效性，但它们对斑块内血管生成 (IPA) 和出血 (IPH) 的影响仍不清楚。因此，我们区分了他汀类药物对 IPA 和 IPH 的降脂依赖性和独立作用。

方法和结果

由于 ApoE 和 LDLR 的存在，ApoE3*Leiden 小鼠对他汀类药物有反应，但也允许通过饮食滴定血浆胆固醇水平。因此，给 ApoE3*Leiden 小鼠喂食含有或不含阿托伐他汀 (A) 的高胆固醇诱导饮食 (HCD) 或中等胆固醇诱导饮食 (MCD)。小鼠接受静脉移植手术以诱导 IPA 和 IPH 病变。与 HCD 相比，MCD (56%) 和 HCD + A (39%) 的胆固醇水平显着降低，而 MCD 和 HCD + A 之间没有显着差异。与 MCD 和 HCD + A 相比，MCD 和 HCD + A 在血管重塑和炎症方面的减少相似光盘。与 HCD 或 MCD 相比，HCD + A 中的 IPA 显着降低了 30%。与 HCD 相比，阿托伐他汀治疗减少了 34% 的未成熟血管的存在，与 MCD 相比减少了 25%，导致 IPH 显着减少。通过 ECs 增殖和迁移的剂量依赖性减少进一步说明了阿托伐他汀的抗血管生成能力。培养的小鼠主动脉节段在阿托伐他汀治疗后失去发芽能力，并在 VE-钙粘蛋白表达和周细胞覆盖方面增加了 30%。此外，Atorvastatin 抑制 ANGPT2 释放并降低 ECs 中的 VE-Cadherin(Y685)-磷酸化。

结论

由于其降脂能力，阿托伐他汀对血管重塑具有有益作用。阿托伐他汀通过减少新血管的数量对 IPA 和通过增加血管成熟度对 IPH 具有很强的多效性。阿托伐他汀通过抑制 ANGPT2 释放和磷酸 (Y658) 介导的 VE-Cadherin 内化来改善血管成熟。