Defective vascular development in connexin 45-deficient mice.
Defective vascular development in connexin 45-deficient mice.
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发表时间：
2000-10
期刊：
影响因子：
4.6
通讯作者：
O. Krüger;A. Plum;Jung-Sun Kim;E. Winterhager;S. Maxeiner;Gaby Hallas;S. Kirchhoff;O. Traub;W. Lamers;K. Willecke
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作者：
O. Krüger;A. Plum;Jung-Sun Kim;E. Winterhager;S. Maxeiner;Gaby Hallas;S. Kirchhoff;O. Traub;W. Lamers;K. Willecke
为了揭示间隙连接蛋白连接蛋白 45 (Cx45) 的生物学功能，我们生成了 Cx45 缺陷型小鼠，并用 lacZ 报告基因有针对性地替换了 Cx45 编码区。杂合子Cx45(+/)(-)小鼠在血管和内脏平滑肌细胞中表现出报告基因的强表达。 Cx45 缺陷胚胎在血管发育中表现出显着的异常，并在胚胎 (E) 9.5 至 10.5 天之间死亡。内皮细胞的分化和定位似乎正常，但随后的血管发育显示卵黄囊中血管树的形成受损，尿囊间质向内生长和胎盘迷路部分毛细血管形成受损，以及动脉生长停滞，包括胚胎本身主要动脉周围的平滑肌层未能发育。结果，大多数 Cx45 缺陷胚胎的心脏扩张。 Cx45(-)(/)(-)胚胎卵黄囊脉管系统的异常发育可能是由TGFbeta信号传导缺陷引起的，因为与野生型胚胎相比，E9.5 Cx45(-)(/)(-)胚胎卵黄囊上皮层中TGF beta1蛋白的量大幅减少。有缺陷的血管发育伴随着大量的细胞凋亡，这种细胞凋亡在E8.5的一些胚胎中开始，并且在E9.5的胚胎的几乎所有组织中大量存在。我们得出的结论是，在Cx45(-)(/)(-)胚胎中，血管发生是正常的，但随后向成熟血管的转化被中断。不同类型血管的发育受到不同程度的损害，这可能反映了其他连接蛋白的补充。
In order to reveal the biological function(s) of the gap-junction protein connexin 45 (Cx45), we generated Cx45-deficient mice with targeted replacement of the Cx45-coding region with the lacZ reporter gene. Heterozygous Cx45(+/)(-) mice showed strong expression of the reporter gene in vascular and visceral smooth muscle cells. Cx45-deficient embryos exhibited striking abnormalities in vascular development and died between embryonic day (E) 9.5 and 10.5. Differentiation and positioning of endothelial cells appeared to be normal, but subsequent development of blood vessels revealed impaired formation of vascular trees in the yolk sac, impaired allantoic mesenchymal ingrowth and capillary formation in the labyrinthine part of the placenta, and arrest of arterial growth, including a failure to develop a smooth muscle layer surrounding the major arteries of the embryo proper. As a consequence, the hearts of most Cx45-deficient embryos were dilated. The abnormal development of the vasculature in the yolk sac of Cx45(-)(/)(-) embryos could be caused by defective TGFbeta signalling, as the amount of TGF beta1 protein in the epithelial layer of the yolk sac was largely decreased in the E9.5 Cx45(-)(/)(-) embryo, compared with the wild-type embryo. The defective vascular development was accompanied by massive apoptosis, which began in some embryos at E8.5 and was abundant in virtually all tissues of the embryos at E9.5. We conclude that in Cx45(-)(/)(-) embryos, vasculogenesis was normal, but subsequent transformation into mature vessels was interrupted. Development of different types of vessels was impaired to a varying extent, which possibly reflects the complementation by other connexin(s).