Fibronectin in Cell Growth and Vascular Remodeling

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DESCRIPTION (provided by applicant): Vascular remodeling occurs in hypertension, and in other cardiovascular pathologies, including atherosclerosis, restenosis and vein graft stenosis. Vascular remodeling is a response of blood vessels to hemodynamic changes or injury, and can result in compensatory changes in the vessel wall that normalizes wall stress. However, remodeling can also lead to alterations in vessel wall stiffness, and narrowing of the vessel lumen that compromise vascular function. Smooth muscle cell migration and proliferation, and excess production and deposition of extracellular matrix proteins can all contribute to changes in the vasculature that occur during vascular remodeling. Our data show that the extracellular matrix protein, fibronectin, plays a key role in controlling the deposition and stability of extracellular matrix proteins, including collagen I. Our data also demonstrate that the polymerization of fibronectin into the extracellular matrix regulates adhesion-dependent cell growth, cell contractility and cell migration. In the absence of continual fibronectin polymerization, fibronectin fragments accumulate in the extracellular matrix, suggesting that fibronectin polymerization maintains extracellular matrix architecture, in part, by controlling matrix proteolysis. Hence, agents that regulate fibronectin polymerization are likely to be crucial in controlling cell proliferation, migration, and extracellular matrix remodeling, all of which are key components of vascular remodeling. In this application, we will test the hypotheses that fibronectin matrix polymerization controls cell growth and migration by altering the composition and stability of the extracellular matrix, and that inhibition of fibronectin polymerization will reduce the extent of smooth muscle cell hyperplasia and extracellular matrix expansion during vascular remodeling. To accomplish this, we will examine the role of fibronectin matrix polymerization in controlling cell growth, cell migration, and extracellular matrix remodeling in smooth muscle cells cultured in vitro, in isolated arteries maintained in organ culture, and in an in vivo model of vascular remodeling. These studies will provide important insights into the complex interplay between smooth muscle cells and extracellular matrix, which plays a critical role in the development and progression of vascular disease.