Connexin37 Regulates Cell Cycle in the Vasculature

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.

Automated summary

Control of vascular cell growth responses is crucial for the development and maintenance of a healthy vasculature. Connexins, the proteins that make up gap junction channels, play a key role in regulating cell growth in diseases such as cancer, but their involvement in controlling cell growth in the vasculature is not well understood. Connexin37 (Cx37) is one type of connexin expressed in the blood vessels and has a unique ability to transduce flow-sensitive signals and influence the cell cycle status of endothelial and mural cells. This review explores the role of Cx37 in vascular growth, vessel organization, and vascular tone in healthy and diseased blood vessels. The review also proposes a novel mechanism involving phosphorylation-dependent channel conformations of Cx37 that regulate cell cycle progression and discusses the potential of Cx37 as a target for cardiovascular disease treatment. The review concludes by addressing research questions that still need to be answered for the development of therapies targeting Cx37.