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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 The mechanical design of distensible hollow organs such as the heart, vessels, and urinary bladder allows for stretching the wall of the organ to permit filling and contraction to facilitate accommodation and propulsion of fluid. Muscle cells in these organs are responsive to stretch in their microenvironment. Mechanotransduction in the heart and vessels involves growth factor release and activation of a number of signaling cascades. In particular, stretch activation of the mitogen-activated protein (MAP) kinase (MAPK) family can modulate cell proliferation, apoptosis, integrity of the extracellular matrix (ECM), muscle wall development, and homeostasis. As in the heart, partial obstruction and distension models that create excessive bladder wall stretch are used to mimic clinical pathological conditions. These models have shown increased muscle growth, accumulation of ECM structural components such as fibrillar collagen types I and III, 1 and increased matrix metalloproteinase (MMP) activity. 2Appreciation of MMP function has evolved significantly since their description as interstitial collagenases. MMPs exert pleiotropic influences by virtue of their ability to cleave diverse substrates, including not only structural ECM proteins but also growth-factor receptors and pre-

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