Department of Cell and Molecular Biology, Tulane University, New Orleans, Louisiana, USA.
Department of Physiology, University of Arizona, Tucson, Arizona, USA.
J Vasc Res. 2023;60(2):73-86. doi: 10.1159/000525619. Epub 2022 Sep 6.
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.
控制血管细胞生长反应对于维持健康的血管系统至关重要。连接蛋白（构成缝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剂，但它们在控制血管中细胞生长的作用尚未得到充分认识。连接蛋白 37（Cx37）是血管壁中表达的四种连接蛋白亚型之一。它在血管中的主要作用依赖于其独特的能力，即能够将流动敏感信号转导为内皮（可能还有壁细胞）细胞周期状态的变化。在这里，我们回顾了 Cx37 在调节健康和患病血管中的血管生长、血管组织和血管张力方面的作用的现有证据。我们提出了一种新的机制，即 Cx37 通过磷酸化依赖性的转变来实现这一点，这种转变是由于 C 端与细胞周期调节剂相互作用，导致封闭（生长抑制）和多个开放（生长允许）通道构象之间的转换，从而限制或支持细胞周期进程。最后，我们讨论了 Cx37 及其下游信号作为心血管疾病治疗的新潜在靶点，并讨论了仍然挑战此类治疗发展的未解决研究问题。
