This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This proposal seeks to understand the functional roles of the alpha7beta1 integrin in regulating vascular smooth muscle plasticity and in vascular disease. The alpha7beta1 integrin and the dystrophin glycoprotein complex connect muscle cells to their surrounding matrix. Duchenne Muscular Dystrophy (DMD) patients and mdx mice (a model for the human disease) have genetic mutations that result in an absence of dystrophin. DMD is characterized by progressive muscle weakness leading to early death from cardiopulmonary failure. DMD patients exhibit vascular abnormalities caused by weak smooth muscle cell attachment, poor contractile responses and excessive bleeding after surgery. In skeletal muscle of DMD patients and mdx mice, the alpha7beta1integrin is increased and may partially compensate for the absence of the dystrophin complex. Enhanced transgenic expression of the alpha7beta1 integrin in skeletal muscle increases the longevity and decreases the pathology of severely dystrophic mice, supporting the hypothesis that alpha7beta1 and the dystrophin complex functionally overlap. Both dystrophin and the alpha7beta1 integrin are expressed in vascular smooth muscle where they mediate cell attachment to laminin. The dystrophin complex is involved in vascular smooth muscle plasticity and Ca2+ homeostasis. This proposal will test the hypothesis that the alpha7beta1 integrin has a complementary role in regulating vascular smooth muscle cell plasticity. We will use mdx mice to determine if alpha7beta1 levels are increased in vascular smooth muscle in the absence of dystrophin. We will further determine if altered levels of the alpha7beta1 integrin result in alterations of Ca2+ homeostasis, cell contractility, vascular tone, and cell differentiation. Molecules downstream of the integrin will be analyzed to determine the mechanisms by which increased alpha7beta1 compensates for the absence of dystrophin. The alpha7beta1 integrin may play a critical role in vascular plasticity and disease and these studies may shed light on the underlying molecular basis of vascular function.
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