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Biomechanical Forces and Arterial Remodeling |
Multiple interventional strategies have been employed over the last several decades to treat patients with clinically significant arterial stenoses, centered primarily on restoring perfusion to distal arterial beds via bypass grafting or angioplasty. While these therapies have been shown to be effective, their long-term durability is often limited by progressive narrowing within the bypass graft or at the site of the angioplasty. It is this inward remodeling, occurring within the vessel wall in response to the local injury, which limits the durability of these treatments. An association between arterial remodeling and local hemodynamics has been identified; however the biologic mechanisms underlying this observation are only beginning to be understood. Mechanical shear stress, mediated through the endothelium, has been hypothesized to be the major regulator of vascular remodeling. This biologic process may be divided into two components: the detection of signals by the endothelium due to changes in hemodynamics, and the relay of these signals to adjacent cells within the vessel. Both of these areas have been extensively studied, and the cell-cell signaling pathways provide a potential avenue for intervention in this process. Most of the research aimed at understanding the process of intimal hyperplasia and remodeling after arterial injury has focussed on inhibiting smooth muscle cell growth and wall thickening. An alternate strategy, directed towards treatment of developed intimal lesions, is to stimulate atrophy of the intima after luminal narrowing develops. We are currently developing models towards this end. The development of intimal hyperplasia is a balance between smooth muscle cell proliferation and extracellular deposition on one hand, and cell death and matrix degradation on the other. It is the balance between these two processes that regulate the growth or regression of arterial lesions. We have demonstrated this balance between these opposing forces to be linked to the local hemodynamic environment and in particular the imposed shear stress at the blood-artery interface. Increases in blood flow inhibit hyperplasia (with reductions in smooth muscle cell proliferation and increases in cell death), while reductions in blood flow promote hyperplasia (via the opposite effect). As yet undefined are the biochemical signals that control these events.
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