Enhanced responses to angiogenic cues underlie the pathogenesis of hereditary hemorrhagic telangiectasia 2.
Enhanced responses to angiogenic cues underlie the pathogenesis of hereditary hemorrhagic telangiectasia 2.
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DOI：
10.1371/journal.pone.0063138
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Oh SP
中科院分区：
文献类型：
--
作者：
Choi EJ;Kim YH;Choe SW;Tak YG;Garrido-Martin EM;Chang M;Lee YJ;Oh SP
遗传性出血性毛细血管扩张症（HHT）是一种遗传性血管疾病，其中动静脉畸形（AVM）表现在皮肤和多个内脏器官。HHT由内皮糖蛋白（ENG）、激活素受体样激酶1（ALK 1）或SMAD 4的杂合突变引起。ALK 1调节血管生成，但ALK 1在内皮细胞（EC）中的确切功能仍然难以捉摸。由于HHT患者的大多数血管不会产生病理性血管病变，因此除非施加额外的遗传或环境压力，否则ALK 1杂合EC可能是正常的。为了研究Alk 1-null与Alk 1-杂合EC的细胞和生化表型，我们产生了肺EC系，其中可以通过他莫昔芬治疗诱导从Alk 1条件等位基因（Alk 1 2f）到Alk 1-null等位基因（Alk 1 1f）的基因型转换。与Alk 1-het（2 f/1 f）EC相比，Alk 1-null（1 f/1 f）EC在体外对bFGF的反应显示出增加的迁移特性。与亲本2 f/1 f-EC相比，1 f/1 f-EC形成了更致密、更持久的管状网络。有趣的是，BMP-9对SMAD 1/5磷酸化的反应在2 f/1 f-和1 f/1 f-EC中以相当的方式受损，这表明除了SMAD之外的其他因子可能在1 f/1 f-EC中对增强的血管生成活性起关键作用。我们还证明了在体内，Alk 1缺陷的EC表现出高迁移和侵袭性。综上所述，这些数据表明，ALK 1缺陷EC对血管生成信号的反应增强是HHT 2发病机制的基础。
Hereditary Hemorrhagic Telangiectasia (HHT) is a genetic vascular disease in which arteriovenous malformations (AVMs) manifest in skin and multiple visceral organs. HHT is caused by heterozygous mutations in endoglin (ENG), activin receptor-like kinase 1 (ALK1), or SMAD4. ALK1 regulates angiogenesis, but the precise function of ALK1 in endothelial cells (ECs) remains elusive. Since most blood vessels of HHT patients do not produce pathological vascular lesions, ALK1 heterozygous ECs may be normal unless additional genetic or environmental stresses are imposed. To investigate the cellular and biochemical phenotypes of Alk1-null versus Alk1-heterozygous ECs, we have generated pulmonary EC lines in which a genotype switch from the Alk1-conditional allele (Alk1 2f) to the Alk1-null allele (Alk1 1f) can be induced by tamoxifen treatment. Alk1-null (1 f/1 f) ECs displayed increased migratory properties in vitro in response to bFGF compared with Alk1-het (2 f/1 f) ECs. The 1 f/1 f-ECs formed a denser and more persistent tubular network as compared with their parental 2 f/1 f-ECs. Interestingly, the response to BMP-9 on SMAD1/5 phosphorylation was impaired in both 2 f/1 f- and 1 f/1 f-ECs at a comparable manner, suggesting that other factors in addition to SMADs may play a crucial role for enhanced angiogenic activity in 1 f/1 f-ECs. We also demonstrated in vivo that Alk1-deficient ECs exhibited high migratory and invasive properties. Taken together, these data suggest that enhanced responses to angiogenic cues in ALK1-deficient ECs underlie the pathogenesis of HHT2.
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影响因子：
37.8
作者：
Hong KH;Lee YJ;Lee E;Park SO;Han C;Beppu H;Li E;Raizada MK;Bloch KD;Oh SP
通讯作者：
Oh SP
影响因子：
6
作者：
Bourdeau, A;Cymerman, U;Letarte, M
通讯作者：
Letarte, M
影响因子：
16
作者：
Goumans, MJ;Valdimarsdottir, G;ten Dijke, P
通讯作者：
ten Dijke, P
影响因子：
4.8
作者：
Brown, MA;Zhao, QH;Choe, S
通讯作者：
Choe, S
影响因子：
11.4
作者：
Goumans, MJ;Valdimarsdottir, G;ten Dijke, P
通讯作者：
ten Dijke, P