Cytoskeleton remodeling regulates contractile function and mechanosensing in vascular smooth muscle
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abstract
Over 80% of the patients with thoracic aneurysm and aortic dissection (TAAD) disease present a phenotype characterized by progressive enlargement of the ascending aorta, which will predispose the aorta to rupture leading to sudden death. Vascular smooth muscle (VSM) cells in the aorta play an integral role in regulating vessel wall contractility and matrix deposition in the medial layer. Recent studies show that mutations in genes associated with actomyosin apparatus (i.e., ACTA2), reduce VSM cell contractility increasing susceptibility to TAAD. Upregulation of other actin isoforms in a mouse model of TAAD did not rescue contractility suggesting that other actin isoforms cannot fully substitute for SMalpha-actin. Therefore, there is a critical need to determine how these actin isoforms affect cell stiffness and contractility, cell adhesion, and, ultimately, vessel wall function. The objective of this proposal is to determine how actin isoforms contribute to the regulation of contractile function and mechanosensing of VSM cells in TAAD. Our central hypothesis is that contractile function and mechanosensing in VSM cells is dependent on actin isoform-specific regulation of cell stiffness and adhesion. Our approach will involve the use of real-time, high-resolution fluorescence and atomic force microscopy (AFM) in live cells, and ex-vivo functional experiments in aortic rings from mice. The rationale for the proposed research is that a mechanistic understanding of the specific roles of actin-isoforms in regulating VSM cell contraction and adhesion will lead to identification of molecular targets for developing interventions to prevent or delay TAAD. The hypothesis will be tested by pursuing the following two specific aims: 1) Identify specific roles of SKalpha- and SMgamma-actin in cytoskeletal remodeling and contractility when SMalpha-actin filaments are disrupted; and 2) Determine the mechanisms by which SMalpha-actin disruption induces decreased adhesion strength to the matrix. This research is significant because understanding of the mechanisms regulating VSM cell contractility and adhesion in TAAD will fill critical gaps in knowledge regarding disease progression. The proposed research is innovative because it represents a new direction for studying TAAD aimed at addressing the contribution of pathological VSM cell remodeling to TAAD. (AHA Program: Transformational Project Award)
