Control of vascular cell growth responses is critical for development and maintenance of a healthy vasculature. Connexins – the proteins comprising gap junction channels – are key regulators of cell growth in diseases such as cancer, but their involvement in controlling cell growth in the vasculature is less well appreciated. Connexin37 (Cx37) is one of four connexin isotypes expressed in the vessel wall. Its primary role in blood vessels relies on its unique ability to transduce flow-sensitive signals into changes in cell cycle status of endothelial (and perhaps, mural) cells. Here, we review available evidence for Cx37’s role in the regulation of vascular growth, vessel organization, and vascular tone in healthy and diseased vasculature. We propose a novel mechanism whereby Cx37 accomplishes this with a phosphorylation-dependent transition between closed (growth-suppressive) and multiple open (growth-permissive) channel conformations that result from interactions of the C-terminus with cell-cycle regulators to limit or support cell cycle progression. Lastly, we discuss Cx37 and its downstream signaling as a novel potential target in the treatment of cardiovascular disease, and we address outstanding research questions that still challenge the development of such therapies.
J Vasc Res

中文翻译：

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Connexin37 调节脉管系统中的细胞周期

控制血管细胞生长反应对于健康脉管系统的发育和维持至关重要。连接蛋白——构成间隙连接通道的蛋白质——是癌症等疾病中细胞生长的关键调节因子，但它们在控制脉管系统细胞生长方面的作用却鲜为人知。Connexin37 (Cx37) 是在血管壁中表达的四种连接蛋白同种型之一。它在血管中的主要作用依赖于其将流敏感信号转导为内皮细胞（也许还有壁细胞）细胞周期状态变化的独特能力。在这里，我们回顾了 Cx37 在健康和患病脉管系统中血管生长、血管组织和血管张力调节中的作用的现有证据。我们提出了一种新的机制，通过该机制，Cx37 通过封闭（生长抑制）和多个开放（生长允许）通道构象之间的磷酸化依赖性转变来实现这一目标，这种转变是由 C 末端与细胞周期调节因子相互作用产生的，以限制或支持细胞周期进展。最后，我们讨论了 Cx37 及其下游信号传导作为治疗心血管疾病的新潜在靶点，并解决了仍然挑战此类疗法开发的突出研究问题。
瓦斯克研究杂志