Cerebral cavernous malformations proteins inhibit Rho kinase to stabilize vascular integrity.
Cerebral cavernous malformations proteins inhibit Rho kinase to stabilize vascular integrity.
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DOI：
10.1084/jem.20091258
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发表时间：
2010-04-12
期刊：
影响因子：
--
通讯作者：
Ginsberg MH
中科院分区：
文献类型：
--
作者：
Stockton RA;Shenkar R;Awad IA;Ginsberg MH
内皮细胞-细胞连接调节血管通透性、血管发生和血管生成。人类家族性脑海绵状血管畸形（CCM）是由CCM 2（malcavernin，OSM，MGC 4607），PDCD 10（CCM 3）或KRIT 1（CCM 1）突变引起的，KRIT 1是一种稳定内皮细胞-细胞连接的Rap 1效应子。KRIT 1或CCM 2的纯合缺失在小鼠和斑马鱼中产生致命的血管表型。我们报告说，KRIT 1和CCM 2蛋白的物理相互作用是必要的内皮细胞-细胞交界处的本地化，和缺乏蛋白质不稳定的屏障功能，通过维持活性的RhoA及其效应Rho激酶（ROCK）。蛋白质单倍体不足的Krit 1 +/−或Ccm 2 +/−小鼠内皮细胞在体外表现出单层通透性增加，Krit 1 +/−和Ccm 2 +/−小鼠在体内表现出血管渗漏增加，可通过ROCK抑制剂法舒地尔逆转。此外，我们发现，ROCK过度活跃发生在散发性和家族性人CCM内皮细胞的肌球蛋白轻链磷酸化增加判断。这些数据证实KRIT 1-CCM 2相互作用通过抑制Rho/ROCK信号传导调节血管屏障功能，并且该途径在人CCM内皮中失调，并且它们表明法舒地尔可以改善CCM疾病和血管渗漏。
Endothelial cell–cell junctions regulate vascular permeability, vasculogenesis, and angiogenesis. Familial cerebral cavernous malformations (CCMs) in humans result from mutations of CCM2 (malcavernin, OSM, MGC4607), PDCD10 (CCM3), or KRIT1 (CCM1), a Rap1 effector which stabilizes endothelial cell–cell junctions. Homozygous loss of KRIT1 or CCM2 produces lethal vascular phenotypes in mice and zebrafish. We report that the physical interaction of KRIT1 and CCM2 proteins is required for endothelial cell–cell junctional localization, and lack of either protein destabilizes barrier function by sustaining activity of RhoA and its effector Rho kinase (ROCK). Protein haploinsufficient Krit1+/− or Ccm2+/− mouse endothelial cells manifested increased monolayer permeability in vitro, and both Krit1+/− and Ccm2+/− mice exhibited increased vascular leak in vivo, reversible by fasudil, a ROCK inhibitor. Furthermore, we show that ROCK hyperactivity occurs in sporadic and familial human CCM endothelium as judged by increased phosphorylation of myosin light chain. These data establish that KRIT1–CCM2 interaction regulates vascular barrier function by suppressing Rho/ROCK signaling and that this pathway is dysregulated in human CCM endothelium, and they suggest that fasudil could ameliorate both CCM disease and vascular leak.
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