Karnik Satyajit K, Brooke Benjamin S, Bayes-Genis Antonio, Sorensen Lise, Wythe Joshua D, Schwartz Robert S, Keating Mark T, Li Dean Y
Program in Human Molecular Biology and Genetics, University of Utah, Salt Lake City, UT, USA.
Development. 2003 Jan;130(2):411-23. doi: 10.1242/dev.00223.
Vascular proliferative diseases such as atherosclerosis and coronary restenosis are leading causes of morbidity and mortality in developed nations. Common features associated with these heterogeneous disorders involve phenotypic modulation and subsequent abnormal proliferation and migration of vascular smooth muscle cells into the arterial lumen, leading to neointimal formation and vascular stenosis. This fibrocellular response has largely been attributed to the release of multiple cytokines and growth factors by inflammatory cells. Previously, we demonstrated that the disruption of the elastin matrix leads to defective arterial morphogenesis. Here, we propose that elastin is a potent autocrine regulator of vascular smooth muscle cell activity and that this regulation is important for preventing fibrocellular pathology. Using vascular smooth muscle cells from mice lacking elastin (Eln(-/-)), we show that elastin induces actin stress fiber organization, inhibits proliferation, regulates migration and signals via a non-integrin, heterotrimeric G-protein-coupled pathway. In a porcine coronary model of restenosis, the therapeutic delivery of exogenous elastin to injured vessels in vivo significantly reduces neointimal formation. These findings indicate that elastin stabilizes the arterial structure by inducing a quiescent contractile state in vascular smooth muscle cells. Together, this work demonstrates that signaling pathways crucial for arterial morphogenesis can play an important role in the pathogenesis and treatment of vascular disease.
诸如动脉粥样硬化和冠状动脉再狭窄等血管增殖性疾病是发达国家发病和死亡的主要原因。与这些异质性疾病相关的共同特征包括表型调节以及随后血管平滑肌细胞向动脉管腔的异常增殖和迁移，导致内膜形成和血管狭窄。这种纤维细胞反应很大程度上归因于炎症细胞释放多种细胞因子和生长因子。此前，我们证明弹性蛋白基质的破坏会导致动脉形态发生缺陷。在此，我们提出弹性蛋白是血管平滑肌细胞活性的有效自分泌调节因子，并且这种调节对于预防纤维细胞病变很重要。利用来自缺乏弹性蛋白的小鼠（Eln(-/-)）的血管平滑肌细胞，我们表明弹性蛋白诱导肌动蛋白应力纤维组织化，抑制增殖，调节迁移并通过非整合素、异源三聚体G蛋白偶联途径发出信号。在猪冠状动脉再狭窄模型中，体内向受损血管治疗性递送外源性弹性蛋白可显著减少内膜形成。这些发现表明弹性蛋白通过在血管平滑肌细胞中诱导静止收缩状态来稳定动脉结构。总之，这项工作表明对动脉形态发生至关重要的信号通路在血管疾病的发病机制和治疗中可以发挥重要作用。
