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首页> 外文期刊>Cell and Tissue Research >β-adrenergic receptor antagonists inhibit vasculogenesis of embryonic stem cells by downregulation of nitric oxide generation and interference with VEGF signalling.
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β-adrenergic receptor antagonists inhibit vasculogenesis of embryonic stem cells by downregulation of nitric oxide generation and interference with VEGF signalling.

机译:β-肾上腺素能受体拮抗剂通过一氧化氮生成的下调和对VEGF信号的干扰来抑制胚胎干细胞的血管生成。

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The β-adrenoceptor antagonist Propranolol has been successfully used to treat infantile hemangioma. However, its mechanism of action is so far unknown. The hypothesis of this research was that β-adrenoceptor antagonists may interfere with endothelial cell differentiation of stem cells. Specifically, the effects of the non-specific β-adrenergic receptor (β-adrenoceptor) antagonist Propranolol, the β1-adrenoceptor-specific antagonist Atenolol and the β2-adrenoceptor-specific antagonist ICI118,551 on vasculogenesis of mouse embryonic stem (ES) cells were investigated. All three β-blockers dose-dependently downregulated formation of capillary structures in ES cell-derived embryoid bodies and decreased the expression of the vascular cell markers CD31 and VE-cadherin. Furthermore, β-blockers downregulated the expression of fibroblast growth factor-2 (FGF-2), hypoxia inducible factor-1α (HIF-1α), vascular endothelial growth factor 165 (VEGF165), VEGF receptor 2 (VEGF-R2) and phospho VEGF-R2, as well as neuropilin 1 (NRP1) and plexin-B1 which are essential modulators of embryonic angiogenesis with additional roles in vessel remodelling and arteriogenesis. Under conditions of β-adrenoceptor inhibition, the endogenous generation of nitric oxide (NO) as well as the phosphorylation of endothelial nitric oxide synthase (eNOS) was decreased in embryoid bodies, whereas an increase in NO generation was observed with the NO donor S-nitroso-N-acetyl-D,L-penicillamine (SNAP). Consequently, vasculogenesis of ES cells was restored upon treatment of differentiating ES cells with β-adrenoceptor antagonists in the presence of NO donor. In summary, our data suggest that β-blockers impair vasculogenesis of ES cells by interfering with NO generation which could be the explanation for their anti-angiogenic effects in infantile hemangioma.
机译:β-肾上腺素能受体拮抗剂普萘洛尔已成功用于治疗婴儿血管瘤。但是,其作用机理迄今尚不清楚。该研究的假设是β-肾上腺素能受体拮抗剂可能干扰干细胞的内皮细胞分化。具体来说,非特异性β-肾上腺素能受体(Properanol),β1-肾上腺素能受体特异性拮抗剂Atenolol和β2-肾上腺素能受体特异性拮抗剂ICI118,551对小鼠胚胎干(ES)细胞血管生成的影响被调查了。所有这三种β受体阻滞剂均剂量依赖性地下调了ES细胞来源的胚状体中毛细血管结构的形成,并降低了血管细胞标志物CD31和VE-钙黏着蛋白的表达。此外,β受体阻滞剂下调了成纤维细胞生长因子2(FGF-2),缺氧诱导因子1α(HIF-1α),血管内皮生长因子165(VEGF165),VEGF受体2(VEGF-R2)和磷酸化的表达。 VEGF-R2以及神经菌素1(NRP1)和神经丛蛋白B1是胚胎性血管新生的重要调节剂,在血管重塑和动脉生成中具有额外作用。在β-肾上腺素受体抑制的条件下,胚状体中一氧化氮(NO)的内源性生成以及内皮型一氧化氮合酶(eNOS)的磷酸化减少,而NO供体S-则观察到NO生成的增加亚硝基-N-乙酰基-D,L-青霉胺(SNAP)。因此,在NO供体存在下,用β-肾上腺素能受体拮抗剂处理分化的ES细胞后,ES细胞的血管生成得以恢复。总而言之,我们的数据表明,β受体阻滞剂通过干扰NO生成而损害ES细胞的血管生成,这可能是其在婴儿血管瘤中的抗血管生成作用的解释。

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