Mechanotransduction of extracellular signal-regulated kinases 1 and 2 mitogen-activated protein kinase activity in smooth muscle is dependent on the extracellular matrix and regulated by matrix metalloproteinases
Mechanotransduction of extracellular signal-regulated kinases 1 and 2 mitogen-activated protein kinase activity in smooth muscle is dependent on the extracellular matrix and regulated by matrix metalloproteinases
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DOI：
10.2353/ajpath.2006.050969
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发表时间：
2006-08-01
影响因子：
6
通讯作者：
Bagli, Darius J.
中科院分区：
文献类型：
--
作者：
Aitken, Karen J.;Block, Gregory;Bagli, Darius J.
心血管和泌尿系统可膨胀中空器官的壁过度拉伸可激活基质金属蛋白酶（MMPs），从而释放基质新表位和生长因子配体，导致ERK1/2活化。然而，MMPs在膀胱ERK1/2信号的机械转导中的作用尚不清楚。我们检查了膀胱随时间持续膨胀，这为平滑肌机械转导研究提供了一个新的平台。体外膀胱膨胀导致增殖和MMP活性增加。膨胀膀胱与未膨胀膀胱条件培养基诱导膀胱平滑肌细胞（BSMCs）增殖。当从膨胀的膀胱中提取的条件培养基用于蛋白水解I型胶原基质时，基质增强了BSMC的增殖，如果膀胱在广谱MMP抑制剂的存在下膨胀，则BSMC的增殖受到抑制。离体膀胱的膨胀也会诱导ERK1/2原位磷酸化，这依赖于完整膀胱中的MMP活性。同样，体外拉伸BSMCs在离散力学条件下诱导ERK1/2激活和ERK1/2依赖性增殖增加，膨胀条件培养基本身诱导BSMCs中mmp依赖性ERK1/2激活。总之，膀胱组织和BSMCs中拉伸诱导的增殖和ERK1/2信号可能依赖于分泌的MMP活性。确定MMPs和ERK1/2之间的中介可能阐明膀胱平滑肌机械转导的新机制。
Excessive wall stretch of distensible hollow organs in cardiovascular and urinary systems can activate matrix metalloproteinases (MMPs), thereby releasing matrix neoepitopes and growth factor ligands, leading to ERK1/2 activation. However, the role of MMPs in mechanotransduction of ERK1/2 signaling in the bladder is unknown. We examined bladders undergoing sustained distension over time, which provides a novel platform for smooth muscle mechanotransduction studies. Bladder distension ex vivo caused increased proliferation and MMP activity. Conditioned medium from distended compared with undistended bladders induced proliferation in bladder smooth muscle cells (BSMCs). When conditioned medium from distended bladders was used to proteolyze collagen type I matrices, matrices augmented BSMC proliferation, which was inhibited if bladders were distended in presence of broad-spectrum MMP inhibitors. Distension of ex vivo bladders also induced ERK1/2 phosphorylation in situ, which was dependent on MMP activity in the intact bladder. Similarly, stretching BSMCs in vitro induced increases in ERK1/2 activation and ERK1/2-dependent proliferation under discrete mechanical conditions, and distension conditioned medium itself induced MMP-dependent ERK1/2 activation in BSMCs. Overall, stretch-induced proliferation and ERK1/2 signaling in bladder tissue and BSMCs likely depend on secreted MMP activity. Identification of intermediaries between MMPs and ERK1/2 may elaborate novel mechanisms underlying mechanotransduction in bladder smooth muscle.