Role of intimal stiffness in endothelial-mesenchymal transition and atherosclerosis progression
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abstract
Loss of arterial elasticity, resulting from progressive increase in intimal stiffness and heightened intracellular tension, is considered a critical, cholesterol-independent risk factor for cardiovascular disease. However, the molecular underpinnings of the reciprocal interdependence between intimal and endothelial cell stiffening remain poorly defined. Changes associated with endothelial activation are also attributes of endothelial-to-mesenchymal transition (EndoMT), a process contributing to atherosclerosis. The Nck family of adaptors, critically involved in cytoskeletal remodeling, is required for cardiovascular development and EndoMT. We hypothesize that Nck drives EndoMT in response to intimal stiffening and thereby promotes a pro-inflammatory, dysfunctional endothelium that primes atherosclerosis development. Aim 1 will address the role of endothelial Nck in atherosclerosis progression by comparing atherosclerosis metrics and arterial biomechanics in ApoE-deficient mice with or without inducible, endothelial-specific deletion of Nck. Aim 2 will identify underlying atherogenic mechanisms by determining the contribution of endothelial Nck to activation of the RhoA/FAK pathway in response to substratum stiffening. These results are expected to have an important positive impact on the subsequent development of novel therapeutics that, by modulating endothelial cell compliance, may prevent progression of vascular disease. (AHA Program: Grant-in-Aid)
