Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.
Am J Pathol. 2011 Jun;178(6):2536-46. doi: 10.1016/j.ajpath.2011.02.045.
Gap junction proteins (connexins) facilitate intercellular communication and serve several roles in regulation of tissue function and remodeling. To examine the physiologic effects of depleting two prominent endothelial connexins, Cx40 and Cx43, transgenic mice were generated by breeding Cx40-deficient mice (Cx40(-/-)) with a vascular endothelial cell (VEC)-specific Cx43-deficient mouse strain (VEC Cx43(-/-)) to produce double-connexin knockout mice (VEC Cx43(-/-)/Cx40(-/-)). The life span in VEC Cx43(-/-)/Cx40(-/-) mice was dramatically shortened, which correlated with severe spontaneous lung abnormalities as the mice aged including increased fibrosis, aberrant alveolar remodeling, and increased lung fibroblast content. Moreover, VEC Cx43(-/-)/Cx40(-/-) mice exhibited cardiac hypertrophy and hypertension. Because VEC Cx43(-/-)/Cx40(-/-) mice demonstrated phenotypic hallmarks that were remarkably similar to those in mice deficient in caveolin-1, pulmonary caveolin expression was examined. Lungs from VEC Cx43(-/-)/Cx40(-/-) mice demonstrated significantly decreased expression of caveolin-1 and caveolin-2. This suggests that expression of caveolin-1 may be linked to expression of Cx40 and endothelial Cx43. Moreover, the phenotype of caveolin-1(-/-) mice and VEC Cx43(-/-)/Cx40(-/-) mice may arise via a common mechanism.
间隙连接蛋白（连接蛋白）促进细胞间通讯，并在调节组织功能和重塑中发挥多种作用。为了研究耗尽两种主要的内皮连接蛋白 Cx40 和 Cx43 的生理效应，通过将 Cx40 缺陷型小鼠（Cx40(-/-)）与血管内皮细胞（VEC）特异性 Cx43 缺陷型小鼠品系（VEC Cx43(-/-)）杂交，产生双连接蛋白敲除小鼠（VEC Cx43(-/-)/Cx40(-/-)）。VEC Cx43(-/-)/Cx40(-/-) 小鼠的寿命显著缩短，这与随着年龄的增长，小鼠出现严重的自发性肺异常相关，包括纤维化增加、肺泡结构异常和肺成纤维细胞含量增加。此外，VEC Cx43(-/-)/Cx40(-/-) 小鼠还表现出心脏肥大和高血压。由于 VEC Cx43(-/-)/Cx40(-/-) 小鼠表现出与 Cav-1 缺陷型小鼠非常相似的表型特征，因此检查了肺 Cav-1 的表达。VEC Cx43(-/-)/Cx40(-/-) 小鼠的肺组织中 Cav-1 和 Cav-2 的表达显著降低。这表明 Cav-1 的表达可能与 Cx40 和内皮 Cx43 的表达有关。此外，Cav-1(-/-) 小鼠和 VEC Cx43(-/-)/Cx40(-/-) 小鼠的表型可能通过共同的机制产生。
