Radiotherapy suppresses angiogenesis in mice through TGF-betaRI/ALK5-dependent inhibition of endothelial cell sprouting.
Radiotherapy suppresses angiogenesis in mice through TGF-betaRI/ALK5-dependent inhibition of endothelial cell sprouting.
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DOI：
10.1371/journal.pone.0011084
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发表时间：
2010-06-11
期刊：
影响因子：
3.7
通讯作者：
Rüegg C
中科院分区：
文献类型：
--
作者：
Imaizumi N;Monnier Y;Hegi M;Mirimanoff RO;Rüegg C
放射疗法广泛用于治疗癌症。虽然快速分裂的癌细胞自然被认为是放射治疗的主要目标，但新出现的证据表明放射治疗也会影响内皮细胞功能，并可能影响其血管生成能力。尽管具有临床相关性，但放射治疗的这种假定的抗血管生成作用尚未得到彻底的表征。我们利用体内、离体和体外实验模型并结合遗传和药理学干预研究了电离辐射对血管生成的影响。在这里，我们表明，高剂量电离辐射局部抑制小鼠体内 VEGF 和 FGF-2 诱导的基质胶栓塞血管生成，并防止体内或离体照射后小鼠主动脉环内皮细胞的萌芽。体外暴露于电离辐射的静态人内皮细胞抵抗细胞凋亡，表现出出芽、迁移和增殖能力降低，表现出对基质蛋白的粘附增强，并经历过早衰老。辐射诱导内皮细胞中 P53 和 P21 蛋白的表达，但 p53 或 p21 缺陷以及 P21 沉默并不能阻止辐射诱导的出芽或增殖抑制。辐射在体内皮肤和体外内皮细胞中诱导 Smad-2 磷酸化。抑制 TGF-β I 型受体 ALK5 可在体外挽救有缺陷的内皮细胞出芽和迁移，但不能挽救增殖，并在体内恢复受辐射小鼠中有缺陷的基质胶塞血管生成。然而，ALK5 抑制并不能挽救增殖缺陷。 Notch 信号传导已知会阻碍血管生成，可通过辐射激活，但其单独抑制或与 ALK5 抑制联合使用并不能挽救抑制的增殖。这些结果表明，静止内皮细胞的照射会抑制随后的血管生成，并且 ALK5 是这种抑制的关键介质。这些结果扩展了我们对放疗引起的内皮功能障碍的理解，这些功能障碍与放疗的治疗效果和不良反应相关。
Radiotherapy is widely used to treat cancer. While rapidly dividing cancer cells are naturally considered the main target of radiotherapy, emerging evidence indicates that radiotherapy also affects endothelial cell functions, and possibly also their angiogenic capacity. In spite of its clinical relevance, such putative anti-angiogenic effect of radiotherapy has not been thoroughly characterized. We have investigated the effect of ionizing radiation on angiogenesis using in vivo, ex vivo and in vitro experimental models in combination with genetic and pharmacological interventions. Here we show that high doses ionizing radiation locally suppressed VEGF- and FGF-2-induced Matrigel plug angiogenesis in mice in vivo and prevented endothelial cell sprouting from mouse aortic rings following in vivo or ex vivo irradiation. Quiescent human endothelial cells exposed to ionizing radiation in vitro resisted apoptosis, demonstrated reduced sprouting, migration and proliferation capacities, showed enhanced adhesion to matrix proteins, and underwent premature senescence. Irradiation induced the expression of P53 and P21 proteins in endothelial cells, but p53 or p21 deficiency and P21 silencing did not prevent radiation-induced inhibition of sprouting or proliferation. Radiation induced Smad-2 phosphorylation in skin in vivo and in endothelial cells in vitro. Inhibition of the TGF-β type I receptor ALK5 rescued deficient endothelial cell sprouting and migration but not proliferation in vitro and restored defective Matrigel plug angiogenesis in irradiated mice in vivo. ALK5 inhibition, however, did not rescue deficient proliferation. Notch signaling, known to hinder angiogenesis, was activated by radiation but its inhibition, alone or in combination with ALK5 inhibition, did not rescue suppressed proliferation. These results demonstrate that irradiation of quiescent endothelial cells suppresses subsequent angiogenesis and that ALK5 is a critical mediator of this suppression. These results extend our understanding of radiotherapy-induced endothelial dysfunctions, relevant to both therapeutic and unwanted effects of radiotherapy.
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