缬沙坦通过 Akt 通路损害间充质干细胞的血管生成。

Valsartan impairs angiogenesis of mesenchymal stem cells through Akt pathway.

机构信息

Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Kaohsiung, Taiwan.

出版信息

Int J Cardiol. 2013 Sep 10;167(6):2765-74. doi: 10.1016/j.ijcard.2012.06.128. Epub 2012 Jul 16.

DOI:10.1016/j.ijcard.2012.06.128

PMID:22805546

Abstract

BACKGROUND

Angiotensin II (AngII) reportedly enhances stem cell proliferation, and type 1 angiotensin II receptor (AT1R) antagonists reduce angiogenesis in a rodent hindlimb ischemic model. Whether AT1R antagonists can alter the angiogenic activity of bone-marrow mesenchymal stem cells (BMSCs) is unknown. The purpose of this study is to investigate whether AT1R antagonists can alter the angiogenic activity of BMSCs and explore the potential mechanism for such an action.

METHODS

Mouse BMSCs were isolated and treated with AngII, an AT1R antagonist, and a type 2 angiotensin II receptor (AT2R) antagonist. Angiogenic activity of BMSCs was detected by vascular endothelial growth factor (VEGF) secretion and tube formation of human umbilical vein endothelial cells (HUVECs). BMSCs isolated from enhanced green fluorescent protein (eGFP)-transgenic mice were allografted into ischemic hindlimbs in mice.

RESULTS

The BMSCs constitutively expressed AT1Rs and AT2Rs. AngII treatment significantly increased VEGF secretion by BMSCs. Valsartan (AT1R antagonist) but not PD123319 (AT2R antagonist) treatment attenuated the AngII-induced promotion of VEGF synthesis by BMSCs. The AngII and AngII receptor antagonist control of angiogenic activity of BMSCs were confirmed by tube formation of HUVECs. AngII treatment promoted phosphorylated Ser473 Akt abundance in BMSCs. RNA interference of an isoform of AT1R, valsartan, and wortmannin treatments attenuated AngII-induced Akt phosphorylation. Allograft of BMSCs significantly increased blood flow and VEGF expression in the gastrocnemius muscles of ischemic hindlimbs, which was attenuated after valsartan treatment.

CONCLUSIONS

AT1R antagonists, via AT-1R/PI3K/Akt pathways, impair the AngII-induced promotion of angiogenic activity of mouse BMSCs.

摘要

背景

据报道，血管紧张素 II（AngII）可增强干细胞增殖，而 1 型血管紧张素 II 受体（AT1R）拮抗剂可减少啮齿动物后肢缺血模型中的血管生成。AT1R 拮抗剂是否可以改变骨髓间充质干细胞（BMSCs）的血管生成活性尚不清楚。本研究旨在探讨 AT1R 拮抗剂是否可以改变 BMSCs 的血管生成活性，并探讨其作用的潜在机制。

方法

分离培养小鼠 BMSCs，用血管紧张素 II（AngII）、AT1R 拮抗剂和血管紧张素 II 型受体（AT2R）拮抗剂处理。通过血管内皮生长因子（VEGF）分泌和人脐静脉内皮细胞（HUVECs）管形成检测 BMSCs 的血管生成活性。将增强型绿色荧光蛋白（eGFP）转基因小鼠分离的 BMSCs 同种异体移植到小鼠缺血后肢。

结果

BMSCs 持续表达 AT1R 和 AT2R。AngII 处理可显著增加 BMSCs 的 VEGF 分泌。缬沙坦（AT1R 拮抗剂）而非 PD123319（AT2R 拮抗剂）处理可减弱 AngII 诱导的 BMSCs 中 VEGF 合成的促进作用。通过 HUVECs 的管形成证实了 AngII 和 AngII 受体拮抗剂对 BMSCs 血管生成活性的控制。AngII 处理可促进 BMSCs 中磷酸化 Ser473 Akt 的丰度。AT1R 异构体的 RNA 干扰、缬沙坦和wortmannin 处理可减弱 AngII 诱导的 Akt 磷酸化。BMSCs 的同种异体移植可显著增加缺血后肢比目鱼肌的血流和 VEGF 表达，而缬沙坦处理可减弱该作用。