Department of Vascular Surgery, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.
Department of Medicine, Centre Hospitalier Universitaire Vaudois (CHUV), Laboratory of Experimental Medicine, c/o Department of Physiology, Bugnon 7a, 1005 Lausanne, Switzerland.
Cardiovasc Res. 2017 Jun 1;113(7):805-816. doi: 10.1093/cvr/cvx079.
Intimal hyperplasia (IH) is an abnormal response to vessel injury characterized by the dedifferentiation, migration, and proliferation of quiescent vascular smooth muscle cells (VSMC) to form a neointima layer. Vascular connexins (Cx) are involved in the pathophysiology of various vascular diseases, and Cx43, the main Cx expressed in VSMC, has been shown to promote VSMC proliferation and IH. The aim of this study was to investigate the participation of another Cx, namely Cx37, in the formation of the neointima layer.
Wild-type (WT) and Cx37-deficient (Cx37-/-) C57BL/6J mice were subjected to carotid artery ligation (CAL), a model of vessel injury and IH. The neointima developed linearly in WT until 28 days post surgery. In contrast, the neointima layer was almost absent 14 days after surgery in Cx37-/- mice, and twice as more developed after 28 days compared to WT mice. This large neointima formation correlated with a two-fold increase in cell proliferation in the media and neointima regions between 14 and 28 days in Cx37-/- mice compared to WT mice. The CAL triggered Cx43 overexpression in the media and neointima layers of ligated carotids in WT mice, and selectively up-regulated Cx37 expression in the media layer, but not in the neointima layer. The de novo expression of Cx37 in human primary VSMC reduced cell proliferation and P-Akt levels, in association with lower Cx43 levels, whereas Cx43 overexpression increased P-Akt levels.
The presence of Cx37 in the media layer of injured arteries restrains VSMC proliferation and limits the development of IH, presumably by interfering with the pro-proliferative effect of Cx43 and the Akt pathway.
内膜增生（IH）是一种对血管损伤的异常反应，其特征是静息血管平滑肌细胞（VSMC）的去分化、迁移和增殖，形成新生内膜层。血管连接蛋白（Cx）参与各种血管疾病的病理生理学过程，Cx43 是 VSMC 中主要表达的 Cx，已被证明可促进 VSMC 增殖和 IH。本研究旨在探讨另一种 Cx，即 Cx37，在新生内膜层形成中的参与作用。
野生型（WT）和 Cx37 缺失型（Cx37-/-）C57BL/6J 小鼠接受颈动脉结扎术（CAL），这是一种血管损伤和 IH 模型。WT 小鼠的新生内膜呈线性生长，直到术后 28 天。相比之下，Cx37-/- 小鼠术后 14 天新生内膜层几乎不存在，而术后 28 天比 WT 小鼠多两倍。这种大量的新生内膜形成与细胞增殖的两倍增加相关，14 至 28 天之间，WT 小鼠的中膜和新生内膜区的 Cx37-/- 小鼠的细胞增殖增加了两倍。CAL 在 WT 小鼠的结扎颈动脉的中膜和新生内膜层中触发 Cx43 过表达，并选择性地上调 Cx37 在中膜层的表达，但不在新生内膜层。在人类原代 VSMC 中，Cx37 的新表达降低了细胞增殖和 P-Akt 水平，与 Cx43 水平降低有关，而 Cx43 过表达则增加了 P-Akt 水平。
在受伤动脉的中膜层存在 Cx37 可抑制 VSMC 增殖并限制 IH 的发展，推测是通过干扰 Cx43 的促增殖作用和 Akt 途径。
