title: Altered Smooth Muscle Cell Force Generation as a Driver of Thoracic Aortic Aneurysms and Dissections.
abstract: The importance of maintaining contractile function in aortic smooth muscle cells (SMCs) is evident by the fact that heterozygous mutations in the major structural proteins or kinases controlling contraction lead to the formation of aneurysms of the ascending thoracic aorta that predispose to life-threatening aortic dissections. Force generation by SMC requires ATP-dependent cyclic interactions between filaments composed of SMC-specific isoforms of α-actin (encoded by ACTA2) and myosin heavy chain (MYH11). ACTA2 and MYH11 mutations are predicted or have been shown to disrupt this cyclic interaction predispose to thoracic aortic disease. Movement of the myosin motor domain is controlled by phosphorylation of the regulatory light chain on the myosin filament, and loss-of-function mutations in the dedicated kinase for this phosphorylation, myosin light chain kinase (MYLK) also predispose to thoracic aortic disease. Finally, a mutation in the cGMP-activated protein kinase (PRKG1) results in constitutive activation of the kinase in the absence of cGMP, thus driving SMC relaxation in part through increased dephosphorylation of the regulatory light chain and predisposes to thoracic aortic disease. Furthermore, SMCs cannot generate force without connections to the extracellular matrix through focal adhesions, and mutations in the major protein in the extracellular matrix, fibrillin-1, linking SMCs to the matrix also cause thoracic aortic disease in individuals with Marfan syndrome. Thus, disruption of the ability of the aortic SMC to generate force through the elastin-contractile units in response to pulsatile blood flow may be a primary driver for thoracic aortic aneurysms and dissections.
authors.affiliation: From the Department of Internal Medicine, McGovern Medical School at The University of Texas Health Science Center at Houston (D.M.M., D.-c.G., E.R.); Department of Molecular Physiology and Biophysics, University of Vermont, Burlington (K.M.T.); Department of Pharmacology and Therapeutics, University of Florida College of Medicine, Gainesville (H.L.S.); and Department of Physiology, University of Texas Southwestern Medical Center, Dallas (K.K. J.T.S.). Dianna.M.Milewicz@uth.tmc.edu.
authors.forename: Dianna M
authors.initials: DM
authors.lastname: Milewicz
authors.affiliation: From the Department of Internal Medicine, McGovern Medical School at The University of Texas Health Science Center at Houston (D.M.M., D.-c.G., E.R.); Department of Molecular Physiology and Biophysics, University of Vermont, Burlington (K.M.T.); Department of Pharmacology and Therapeutics, University of Florida College of Medicine, Gainesville (H.L.S.); and Department of Physiology, University of Texas Southwestern Medical Center, Dallas (K.K. J.T.S.).
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Trybus
authors.affiliation: From the Department of Internal Medicine, McGovern Medical School at The University of Texas Health Science Center at Houston (D.M.M., D.-c.G., E.R.); Department of Molecular Physiology and Biophysics, University of Vermont, Burlington (K.M.T.); Department of Pharmacology and Therapeutics, University of Florida College of Medicine, Gainesville (H.L.S.); and Department of Physiology, University of Texas Southwestern Medical Center, Dallas (K.K. J.T.S.).
authors.forename: Dong-Chuan
authors.initials: DC
authors.lastname: Guo
authors.affiliation: From the Department of Internal Medicine, McGovern Medical School at The University of Texas Health Science Center at Houston (D.M.M., D.-c.G., E.R.); Department of Molecular Physiology and Biophysics, University of Vermont, Burlington (K.M.T.); Department of Pharmacology and Therapeutics, University of Florida College of Medicine, Gainesville (H.L.S.); and Department of Physiology, University of Texas Southwestern Medical Center, Dallas (K.K. J.T.S.).
authors.forename: H Lee
authors.initials: HL
authors.lastname: Sweeney
authors.affiliation: From the Department of Internal Medicine, McGovern Medical School at The University of Texas Health Science Center at Houston (D.M.M., D.-c.G., E.R.); Department of Molecular Physiology and Biophysics, University of Vermont, Burlington (K.M.T.); Department of Pharmacology and Therapeutics, University of Florida College of Medicine, Gainesville (H.L.S.); and Department of Physiology, University of Texas Southwestern Medical Center, Dallas (K.K. J.T.S.).
authors.forename: Ellen
authors.initials: E
authors.lastname: Regalado
authors.affiliation: From the Department of Internal Medicine, McGovern Medical School at The University of Texas Health Science Center at Houston (D.M.M., D.-c.G., E.R.); Department of Molecular Physiology and Biophysics, University of Vermont, Burlington (K.M.T.); Department of Pharmacology and Therapeutics, University of Florida College of Medicine, Gainesville (H.L.S.); and Department of Physiology, University of Texas Southwestern Medical Center, Dallas (K.K. J.T.S.).
authors.forename: Kristine
authors.initials: K
authors.lastname: Kamm
authors.affiliation: From the Department of Internal Medicine, McGovern Medical School at The University of Texas Health Science Center at Houston (D.M.M., D.-c.G., E.R.); Department of Molecular Physiology and Biophysics, University of Vermont, Burlington (K.M.T.); Department of Pharmacology and Therapeutics, University of Florida College of Medicine, Gainesville (H.L.S.); and Department of Physiology, University of Texas Southwestern Medical Center, Dallas (K.K. J.T.S.).
authors.forename: James T
authors.initials: JT
authors.lastname: Stull
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000784:Aortic Dissection / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D000818:Animals; D017545:Aortic Aneurysm, Thoracic / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D062965:Cyclic GMP-Dependent Protein Kinase Type I / Q000235:genetics / Q000378:metabolism; D004108:Dilatation, Pathologic; D004549:Elastin / Q000378:metabolism; D005819:Genetic Markers; D005820:Genetic Testing; D040941:Heredity; D006801:Humans; D040542:Mechanotransduction, Cellular; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D009154:Mutation; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology; D018995:Myosin Heavy Chains / Q000235:genetics / Q000378:metabolism; D009219:Myosin-Light-Chain Kinase / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D011673:Pulsatile Flow; D014661:Vasoconstriction / Q000235:genetics
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; D002135:Calcium-Binding Proteins; D005819:Genetic Markers; C509903:MYH11 protein, human; D004549:Elastin; D062965:Cyclic GMP-Dependent Protein Kinase Type I; C569718:PRKG1 protein, human; C499378:MYLK protein, human; D009219:Myosin-Light-Chain Kinase; D018995:Myosin Heavy Chains
keywords: Marfan syndrome; aortic aneurysm; aortic dissection; mutation; thoracic aorta; vascular smooth muscle cells