Atorvastatin pleiotropically decreases intraplaque angiogenesis and intraplaque haemorrhage by inhibiting ANGPT2 release and VE-Cadherin internalization.
Atorvastatin pleiotropically decreases intraplaque angiogenesis and intraplaque haemorrhage by inhibiting ANGPT2 release and VE-Cadherin internalization.
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DOI：
10.1007/s10456-021-09767-9
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发表时间：
2021-08
期刊：
影响因子：
9.8
通讯作者：
Quax PHA
中科院分区：
文献类型：
--
作者：
Baganha F;de Jong RCM;Peters EA;Voorham W;Jukema JW;Delibegovic M;de Vries MR;Quax PHA
他汀类药物在减少动脉粥样硬化方面具有多效性，但其对斑块内血管生成（IPA）和出血（IPH）的影响尚不清楚。因此，我们区分了他汀类药物对IPA和IPH的降脂依赖性和非依赖性作用。由于存在ApoE和LDLR，ApoE 3 *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，ApoE 3 *Leiden小鼠喂食含或不含阿托伐他汀（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用IPA和IPH诱导损伤。与HCD相比，MCD（56%）和HCD + A（39%）的胆固醇水平显著降低，MCD和HCD + A之间无显著差异。与HCD相比，MCD和HCD + A在血管重塑和炎症方面的减少程度相似。与HCD或MCD相比，HCD + A中的IPA显著降低30%。与HCD相比，阿托伐他汀治疗使未成熟血管的存在减少了34%，与MCD相比减少了25%，从而显着降低了IPH。阿托伐他汀的抗血管生成能力进一步说明了剂量依赖性减少内皮细胞的增殖和迁移。经阿托伐他汀治疗后，培养的小鼠睾丸节段失去了发芽能力，VE-钙粘蛋白表达和周细胞覆盖率增加了30%。此外，阿托伐他汀抑制ANGPT 2的释放，并降低内皮细胞中VE-钙粘蛋白（Y 685）-磷酸化。阿托伐他汀由于其降脂能力而对血管重塑具有有益作用。阿托伐他汀通过减少新生血管的数量对IPA和通过增加血管成熟对IPH具有强烈的多效性作用。阿托伐他汀通过抑制ANGPT 2释放和磷酸化（Y 658）介导的VE-钙粘蛋白内化来改善血管成熟。
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. 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. 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.
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阿托伐他汀通过调节趋化因子和趋化因子受体改善 ApoE 敲除小鼠的斑块稳定性
影响因子：
3.7
作者：
Nie P;Li D;Hu L;Jin S;Yu Y;Cai Z;Shao Q;Shen J;Yi J;Xiao H;Shen L;He B
通讯作者：
He B
影响因子：
4
作者：
Dejana, Elisabetta;Orsenigo, Fabrizio;Lampugnani, Maria Grazia
通讯作者：
Lampugnani, Maria Grazia
影响因子：
37.8
作者：
Landmesser, U;Bahlmann, F;Drexler, H
通讯作者：
Drexler, H
影响因子：
10.8
作者：
Le Dall, Julien;Ho-Tin-Noe, Benoit;Houard, Xavier
通讯作者：
Houard, Xavier
影响因子：
56.9
作者：
Maisonpierre, PC;Suri, C;Yancopoulos, GD
通讯作者：
Yancopoulos, GD