Decreased Krev interaction-trapped 1 expression leads to increased vascular permeability and modifies inflammatory responses in vivo.
Decreased Krev interaction-trapped 1 expression leads to increased vascular permeability and modifies inflammatory responses in vivo.
复制标题
DOI：
10.1161/atvbaha.112.300115
复制
发表时间：
2012-11
期刊：
影响因子：
--
通讯作者：
Glading AJ
中科院分区：
文献类型：
--
作者：
Corr M;Lerman I;Keubel JM;Ronacher L;Misra R;Lund F;Sarelius IH;Glading AJ
血管通透性、白细胞转运和内皮细胞-细胞接触的完整性的调节由复杂的相互调节机制紧密联系在一起。在这里，我们研究了KRIT1在调节这些血管功能中的作用，KRIT1是一种细胞-细胞连接稳定所需的黏附连接辅助蛋白。Krit1+/−小鼠对炎性关节炎被动K/BxN模型和小鼠气囊模型中发现的复杂炎症刺激表现出增强的水肿性反应，但白细胞浸润没有变化。相应地，KRIT1表达减少使基础小动脉和小静脉通透性增加2倍于野生型小鼠，这是通过对完整的提睾肌血管网络的活体显微镜测量的，但这种增加并不伴随着白细胞外渗或激活的增加。肿瘤坏死因子-α的直接刺激导致野生型小鼠通透性增加，但令人惊讶的是，尽管白细胞被广泛激活，Krit1+/−小鼠的通透性并没有比基线水平增加。Krit1+/−骨髓过继移植未能增加野生型小鼠的通透性。然而，KRIT1在造血系中的表达减少抑制了基线通透性的差异。综上所述，我们的数据表明KRIT1在微血管动态平衡和血管对炎症的反应中起着不可或缺的作用。
The regulation of vascular permeability, leukocyte trafficking, and the integrity of endothelial cell-cell contacts are closely linked by a complex mechanism of inter-regulation. Here we investigate the role of KRIT1, an adherens junction accessory protein required for cell-cell junction stability, in the regulating these vascular functions. Krit1+/− mice exhibited an enhanced edematous response to the complex inflammatory stimuli found in the passive K/BxN model of inflammatory arthritis and the murine air pouch model, yet leukocyte infiltration was unchanged. Correspondingly, reduced KRIT1 expression increased baseline arteriole and venule permeability 2-fold over that of wildtype littermates, as measured by intravital microscopy of the intact cremaster muscle vascular network, but this increase was not accompanied by increased leukocyte extravasation or activation. Direct stimulation with tumor necrosis factor–α induced increased permeability in wildtype mice, but surprisingly, no increase over baseline levels was observed in Krit1+/− mice, despite extensive leukocyte activation. Finally, adoptive transfer of Krit1+/− bone marrow failed to increase permeability in wildtype mice. However, reduced expression of KRIT1 in the hematopoietic lineage dampened the differences observed in baseline permeability. Taken together, our data indicate an integral role for KRIT1 in microvessel homeostasis and the vascular response to inflammation.