Activin receptor-like kinase 1 (ALK1) is an endothelial-specific type I receptor of the TGFbeta receptor family that is implicated in angiogenesis and in the pathogenesis of the vascular disease, hereditary hemorrhagic telangiectasia (HHT). In the absence of a specific ligand, ALK1 cellular functions have been mainly studied through the use of a constitutively active form of this receptor (ALK1ca) and are still debated. We previously reported that ALK1ca inhibits proliferation and migration of human endothelial cells suggesting that ALK1 plays an important role in the maturation phase of angiogenesis (Lamouille et al., 2002, Blood 100: 4495-4501). In the present work, we further analyzed the role of ALK1 in the migration of human dermal microvascular endothelial cell (HMVEC-d) and observed that silencing endogenous ALK1 expression with siRNAs accelerates endothelial cell migration in the wound assay. Further, we demonstrate that ALK1-induced inhibition of migration is Smad-independent. Using a panel of kinase inhibitors, we found that HMVEC-d wound closure was completely inhibited by a JNK inhibitor and to a lower degree by an ERK kinase inhibitor. Further, HMVEC-d wounding induced activation of both JNK and ERK, and these were inhibited by ALK1ca expression. Taken together, these results support a significant role for ALK1 as a negative regulator of endothelial cell migration and suggest the implication of JNK and ERK as mediators of this effect.

译文

激活素受体样激酶1 (ALK1) 是TGFbeta受体家族的内皮特异性I型受体,与血管生成和血管疾病的发病机理有关,遗传性出血性毛细血管扩张 (HHT)。在没有特定配体的情况下,主要通过使用该受体的组成型活性形式 (ALK1ca) 来研究ALK1细胞功能,并且仍在争论中。我们先前报道ALK1ca抑制人内皮细胞的增殖和迁移,这表明ALK1在血管生成的成熟期中起重要作用 (Lamouille等人,2002,血液100: 4495-4501)。在目前的工作中,我们进一步分析了ALK1在人真皮微血管内皮细胞 (hmvec-d) 迁移中的作用,并观察到用sirna沉默内源性ALK1表达会加速伤口检测中的内皮细胞迁移。此外,我们证明了ALK1-induced对迁移的抑制是不依赖Smad的。使用一组激酶抑制剂,我们发现hmvec-d伤口闭合被JNK抑制剂完全抑制,而被ERK激酶抑制剂抑制的程度较低。此外,HMVEC-d损伤诱导JNK和ERK的激活,并且这些激活被ALK1ca表达抑制。总之,这些结果支持ALK1作为内皮细胞迁移的负调节剂的重要作用,并暗示JNK和ERK作为这种作用的介体。

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