The role of the endothelium is not just limited to acting as an inert barrier for facilitating blood transport. Endothelial cells (ECs), through expression of a repertoire of angiocrine molecules, regulate metabolic demands in an organ-specific manner. Insulin flux across the endothelium to muscle cells is a rate-limiting process influencing insulin-mediated lowering of blood glucose. Here, we demonstrate that Notch signaling in ECs regulates insulin transport to muscle. Notch signaling activity was higher in ECs isolated from obese mice compared to non-obese. Sustained Notch signaling in ECs lowered insulin sensitivity and increased blood glucose levels. On the contrary, EC-specific inhibition of Notch signaling increased insulin sensitivity and improved glucose tolerance and glucose uptake in muscle in a high-fat diet-induced insulin resistance model. This was associated with increased transcription of Cav1, Cav2, and Cavin1, higher number of caveolae in ECs, and insulin uptake rates, as well as increased microvessel density. These data imply that Notch signaling in the endothelium actively controls insulin sensitivity and glucose homeostasis and may therefore represent a therapeutic target for diabetes.

中文翻译：

---

内皮Notch信号控制胰岛素在肌肉中的运输。

内皮的作用不仅限于充当促进血液运输的惰性屏障。内皮细胞（EC）通过表达血管内分泌分子的全部成分，以器官特异性方式调节代谢需求。跨内皮向肌肉细胞的胰岛素通量是影响胰岛素介导的血糖降低的限速过程。在这里，我们证明EC中的Notch信号调节胰岛素向肌肉的运输。与非肥胖相比，从肥胖小鼠中分离出的EC中的Notch信号活性更高。EC中持续的Notch信号降低了胰岛素敏感性并增加了血糖水平。反之，在高脂饮食诱导的胰岛素抵抗模型中，EC对Notch信号的特异性抑制增加了胰岛素敏感性，并改善了肌肉的葡萄糖耐量和葡萄糖摄取。这与Cav1，Cav2和Cavin1的转录增加，EC中小窝的数量增加，胰岛素摄取率以及微血管密度增加有关。这些数据暗示内皮中的Notch信号传导主动控制胰岛素敏感性和葡萄糖稳态，因此可以代表糖尿病的治疗靶标。