Activin receptor-like kinase 1 inhibits human microvascular endothelial cell migration: Potential roles for JNK and ERK kinase
Activin receptor-like kinase 1 inhibits human microvascular endothelial cell migration: Potential roles for JNK and ERK kinase
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DOI：
10.1002/jcp.21126
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发表时间：
2007-11-01
影响因子：
5.6
通讯作者：
Bailly, Sabine
中科院分区：
文献类型：
--
作者：
David, Laurent;Mallet, Christine;Bailly, Sabine
激活素受体样激酶I （ALK1）是TGF β受体家族的内皮特异性I型受体，参与血管生成和血管疾病遗传性出血性毛细血管扩张症（HHT）的发病。在缺乏特定配体的情况下，ALK1的细胞功能主要通过使用该受体的组成活性形式（ALK1ca）来研究，但仍存在争议。我们之前报道过ALK1ca抑制人内皮细胞的增殖和迁移，表明ALK1在血管生成的成熟阶段起重要作用（Lamouille et al., 2002, Blood 100: 4495-4501）。在本研究中，我们进一步分析了ALK1在人皮肤微血管内皮细胞（HMVEC-d）迁移中的作用，并在伤口实验中发现，用sirna沉默内源性ALK - 1表达可以加速内皮细胞的迁移。此外，我们证明了alk1诱导的迁移抑制是smad无关的。使用一组激酶抑制剂，我们发现hvec -d伤口愈合被JNK抑制剂完全抑制，而ERK激酶抑制剂的抑制程度较低。此外，HMVEC-d损伤诱导JNK和ERK的激活，而这些被alk1ca表达抑制。综上所述，这些结果支持ALK I作为内皮细胞迁移的负调节因子的重要作用，并提示JNK和ERK作为这种作用的介质的含义。
Activin receptor-like kinase I (ALK1) is an endothelial-specific type I receptor of the TGF beta 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 ALK 1 expression with siRNAs accelerates endothelial cell migration in the wound assay. Further, we demonstrate that ALK 1-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 ALK1 ca expression. Taken together, these results support a significant role for ALK I as a negative regulator of endothelial cell migration and suggest the implication of JNK and ERK as mediators of this effect.