RATIONALE Elastin is an important ECM (extracellular matrix) protein in large and small arteries. Vascular smooth muscle cells (SMCs) produce the layered elastic laminae found in elastic arteries but synthesize little elastin in muscular arteries. However, muscular arteries have a well-defined internal elastic lamina (IEL) that separates endothelial cells (ECs) from SMCs. The extent to which ECs contribute elastin to the IEL is unknown. OBJECTIVE To use targeted elastin (Eln) deletion in mice to explore the relative contributions of SMCs and ECs to elastic laminae formation in different arteries. METHODS AND RESULTS We used SMC- and EC-specific Cre recombinase transgenes with a novel floxed Eln allele to focus gene inactivation in mice. Inactivation of Eln in SMCs using Sm22aCre resulted in depletion of elastic laminae in the arterial wall with the exception of the IEL and SMC clusters in the outer media near the adventitia. Inactivation of elastin in ECs using Tie2Cre or Cdh5Cre resulted in normal medial elastin and a typical IEL in elastic arteries. In contrast, the IEL was absent or severely disrupted in muscular arteries. Interruptions in the IEL resulted in neointimal formation in the ascending aorta but not in muscular arteries. CONCLUSIONS Combined with lineage-specific fate mapping systems, our knockout results document an unexpected heterogeneity in vascular cells that produce the elastic laminae. SMCs and ECs can independently form an IEL in most elastic arteries, whereas ECs are the major source of elastin for the IEL in muscular and resistance arteries. Neointimal formation at IEL disruptions in the ascending aorta confirms that the IEL is a critical physical barrier between SMCs and ECs in the large elastic arteries. Our studies provide new information about how SMCs and ECs contribute elastin to the arterial wall and how local elastic laminae defects may contribute to cardiovascular disease.

中文翻译：

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动脉壁发育中弹性片层形成的异质细胞贡献。

RATIONALE弹性蛋白是大小动脉中一种重要的ECM（细胞外基质）蛋白。血管平滑肌细胞（SMC）产生在弹性动脉中发现的分层弹性薄片，但在肌肉动脉中合成了很少的弹性蛋白。但是，肌肉动脉具有定义明确的内部弹性层（IEL），可将内皮细胞（EC）与SMC分离。ECs弹性蛋白对IEL的贡献程度尚不清楚。目的在小鼠中使用靶向弹性蛋白（Eln）缺失来探讨SMC和EC对不同动脉中弹性薄片形成的相对作用。方法和结果我们将SMC和EC特异性的Cre重组酶转基因与一种新型的Ern等位基因一起用于小鼠中的基因失活。使用Sm22aCre使SMC中的Eln失活会导致动脉壁中弹性薄片的消耗，除了外膜附近外层介质中的IEL和SMC簇除外。使用Tie2Cre或Cdh5Cre使EC中的弹性蛋白失活会导致正常的内侧弹性蛋白和弹性动脉中的典型IEL。相反，IEL在肌肉动脉中不存在或严重受损。IEL的中断导致升主动脉形成新内膜，但不引起肌肉动脉。结论结合特定谱系的命运图谱系统，我们的敲除结果表明产生弹性薄片的血管细胞中存在意想不到的异质性。SMC和EC可以在大多数弹性动脉中独立形成IEL，而EC是肌肉和阻力动脉中IEL的弹性蛋白的主要来源。在升主动脉的IEL断裂处新内膜形成证实了IEL是大弹性动脉中SMC与EC之间的关键物理屏障。我们的研究提供了有关SMC和EC如何在动脉壁中产生弹性蛋白以及局部弹性板层缺损如何导致心血管疾病的新信息。