Cadherins, RhoA, and Rac1 are differentially required for stretch-mediated proliferation in endothelial versus smooth muscle cells
Cadherins, RhoA, and Rac1 are differentially required for stretch-mediated proliferation in endothelial versus smooth muscle cells
复制标题
DOI：
10.1161/circresaha.107.158329
复制
发表时间：
2007-08-31
影响因子：
20.1
通讯作者：
Chen, Christopher S.
中科院分区：
文献类型：
--
作者：
Liu, Wendy F.;Nelson, Celeste M.;Chen, Christopher S.
异常的机械力可以触发内皮细胞和平滑肌细胞的异常增殖，如在血管疾病如动脉粥样硬化的进展中所观察到的。先前已经表明，细胞可以通过粘附到细胞外基质来感知物理力，例如拉伸。在这里，我们着手研究细胞间粘附是否也参与将机械拉伸转换为增殖反应。我们发现，内皮细胞和平滑肌细胞都表现出对拉伸反应的增殖增加。使用微图案分离的作用，细胞-细胞粘附细胞-细胞外基质粘附，我们证明，内皮细胞需要细胞-细胞接触和血管内皮钙粘蛋白的参与，以避免伸展成增殖信号。相比之下，平滑肌细胞在不接触相邻细胞的情况下对拉伸做出反应。我们进一步表明，拉伸刺激Rac 1在内皮细胞中的活性，而RhoA在平滑肌细胞中被拉伸激活。通过药理学或腺病毒试剂阻断Rac 1信号传导废除了内皮细胞对拉伸的增殖反应，但在平滑肌细胞中没有。相反，阻断RhoA完全抑制平滑肌细胞的增殖反应，但不抑制内皮细胞。总之，这些数据表明，血管内皮钙粘蛋白在机械转导中具有重要作用，并且内皮细胞和平滑肌细胞使用不同的机制来响应拉伸。
Abnormal mechanical forces can trigger aberrant proliferation of endothelial and smooth muscle cells, as observed in the progression of vascular diseases such as atherosclerosis. It has been previously shown that cells can sense physical forces such as stretch through adhesions to the extracellular matrix. Here, we set out to examine whether cell-cell adhesions are also involved in transducing mechanical stretch into a proliferative response. We found that both endothelial and smooth muscle cells exhibited an increase in proliferation in response to stretch. Using micropatterning to isolate the role of cell-cell adhesion from cell-extracellular matrix adhesion, we demonstrate that endothelial cells required cell-cell contact and vascular endothelial cadherin engagement to transduce stretch into proliferative signals. In contrast, smooth muscle cells responded to stretch without contact to neighboring cells. We further show that stretch stimulated Rac1 activity in endothelial cells, whereas RhoA was activated by stretch in smooth muscle cells. Blocking Rac1 signaling by pharmacological or adenoviral reagents abrogated the proliferative response to stretch in endothelial cells but not in smooth muscle cells. Conversely, blocking RhoA completely inhibited the proliferative response in smooth muscle cells but not in endothelial cells. Together, these data suggest that vascular endothelial cadherin has an important role in mechanotransduction and that endothelial and smooth muscle cells use different mechanisms to respond to stretch.