Mutations in Smooth Muscle Contractile Proteins: Pathways to Vascular Diseases

Summary

Principal Investigator: Dianna M Milewicz
Abstract: Vascular SMCs are arranged circumferentially in arteries in multiple layers, either embedded between layers of elastin lamellae in large elastic arteries or in a matrix of connective tissue in smaller muscular arteries. For contractile function, SMCs express smooth muscle specific isoforms of alpha-actin and Beta-myosin, which multimerize to form thin and thick filaments, respectively. We have determined that mutations in the genes encoding SMC alpha-actin and Beta-myosin, ACTA2 and MYH11, along with the kinase that controls SMC contraction, myosin light chain kinase (MYLK), predispose individuals to vascular diseases, including thoracic aortic aneurysms and aortic dissections and occlusive vascular diseases, such as early onset coronary artery disease and stroke. The Program Project Grant (PPG) will test the hypothesis that the ACTA2, MYH11 and MYLK mutations lead to thoracic aortic and disease and/or occlusive vascular diseases due to a differential SMC response to biomechanical stresses resulting from dysfunction of the contractile unit. We hypothesize that mutations in these genes cause a [unreadable]loss of function[unreadable], specifically loss of regulation or altered force output of contractile unit in SMCs in ascending aorta, resulting in increased biomechanical stresses and activation of SMC pathways leading to thoracic aortic aneurysms and aortic dissections. In contrast, we hypothesize that the occlusive vascular diseases associated with a subset of ACTA2 mutations, and possibly MYH11 variants, result from a SMC "gain of function" in muscular arteries, specifically increased SMC proliferation as a consequence of altered focal adhesions and activation of PDGFR-Beta receptors in response to abnormal cellular force generation. To test these hypotheses. Project 1 and 2 will assess the Impact of ACTA2 and MYH11 genetic variants on kinetics, motility, regulation, and filament formation in vitro. Project 3 will assess age-dependent derangements in specific signaling modules responsible for vasomotor responsiveness in vascular SMCs in mouse models of select ACTA2, MYH11 and MYLK mutations. Project 4 will Investigate SMC cellular pathways leading to thoracic aortic disease and SMC proliferation in these same mouse models.
Funding Period: 2012-08-25 - 2017-07-31
more information: NIH RePORT

Top Publications

  1. pmc Signaling through myosin light chain kinase in smooth muscles
    Ning Gao
    Department of Physiology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA
    J Biol Chem 288:7596-605. 2013
  2. pmc A periodic pattern of evolutionarily conserved basic and acidic residues constitutes the binding interface of actin-tropomyosin
    Bipasha Barua
    Departments of Neuroscience and Cell Biology, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, USA
    J Biol Chem 288:9602-9. 2013
  3. pmc Transgenic mouse α- and β-cardiac myosins containing the R403Q mutation show isoform-dependent transient kinetic differences
    Susan Lowey
    Department of Molecular Physiology and Biophysics, University of Vermont, Burlington, Vermont 05405, USA
    J Biol Chem 288:14780-7. 2013
  4. pmc Smooth muscle hyperplasia due to loss of smooth muscle α-actin is driven by activation of focal adhesion kinase, altered p53 localization and increased levels of platelet-derived growth factor receptor-β
    Christina L Papke
    Department of Internal Medicine, University of Texas Health Science Center at Houston, 6431 Fannin, MSB 6 100, Houston, TX 77030, USA
    Hum Mol Genet 22:3123-37. 2013
  5. ncbi Aortic remodeling after transverse aortic constriction in mice is attenuated with AT1 receptor blockade
    Shao Qing Kuang
    Department of Internal Medicine, University of Texas Health Science Center at Houston, University of Texas Medical Branch, Houston, TX 77030, USA
    Arterioscler Thromb Vasc Biol 33:2172-9. 2013
  6. pmc Recurrent gain-of-function mutation in PRKG1 causes thoracic aortic aneurysms and acute aortic dissections
    Dong Chuan Guo
    Department of Internal Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
    Am J Hum Genet 93:398-404. 2013
  7. pmc Successes and challenges of using whole exome sequencing to identify novel genes underlying an inherited predisposition for thoracic aortic aneurysms and acute aortic dissections
    Dianna M Milewicz
    Division of Medical Genetics, Department of Internal Medicine, University of Texas Health Science Center at Houston UT Health, 6431 Fannin, Suite 6 100, Houston, TX 77030, USA Electronic address
    Trends Cardiovasc Med 24:53-60. 2014
  8. pmc Activation of MRTF-A-dependent gene expression with a small molecule promotes myofibroblast differentiation and wound healing
    Lissette S Velasquez
    Department of Medicine, Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642
    Proc Natl Acad Sci U S A 110:16850-5. 2013
  9. pmc Acute aortic dissections with pregnancy in women with ACTA2 mutations
    Ellen S Regalado
    Department of Internal Medicine, University of Texas Health Science Center at Houston, Houston, Texas
    Am J Med Genet A 164:106-12. 2014

Detail Information

Publications9

  1. pmc Signaling through myosin light chain kinase in smooth muscles
    Ning Gao
    Department of Physiology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA
    J Biol Chem 288:7596-605. 2013
    ..Limiting MLCK activity combined with modest Ca(2+) sensitization responses provide insights into how haploinsufficiency of MLCK may result in contractile dysfunction in vivo, leading to dissections of human thoracic aorta...
  2. pmc A periodic pattern of evolutionarily conserved basic and acidic residues constitutes the binding interface of actin-tropomyosin
    Bipasha Barua
    Departments of Neuroscience and Cell Biology, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, USA
    J Biol Chem 288:9602-9. 2013
    ..Tropomyosin failed to bind mutant actin filaments. Our mutagenesis studies provide the first experimental support for the atomic models of the actin-tropomyosin interface...
  3. pmc Transgenic mouse α- and β-cardiac myosins containing the R403Q mutation show isoform-dependent transient kinetic differences
    Susan Lowey
    Department of Molecular Physiology and Biophysics, University of Vermont, Burlington, Vermont 05405, USA
    J Biol Chem 288:14780-7. 2013
    ..These transient kinetic studies on mouse cardiac myosins provide strong evidence that the functional impact of an FHC mutation on myosin depends on the isoform backbone...
  4. pmc Smooth muscle hyperplasia due to loss of smooth muscle α-actin is driven by activation of focal adhesion kinase, altered p53 localization and increased levels of platelet-derived growth factor receptor-β
    Christina L Papke
    Department of Internal Medicine, University of Texas Health Science Center at Houston, 6431 Fannin, MSB 6 100, Houston, TX 77030, USA
    Hum Mol Genet 22:3123-37. 2013
    ..Loss of α-SMA leads to SMC hyperplasia in vivo and in vitro through a mechanism involving FAK, p53 and Pdgfr-β, supporting the hypothesis that SMC hyperplasia contributes to occlusive lesions in patients with ACTA2 missense mutations. ..
  5. ncbi Aortic remodeling after transverse aortic constriction in mice is attenuated with AT1 receptor blockade
    Shao Qing Kuang
    Department of Internal Medicine, University of Texas Health Science Center at Houston, University of Texas Medical Branch, Houston, TX 77030, USA
    Arterioscler Thromb Vasc Biol 33:2172-9. 2013
    ..We investigated the role of angiotensin II type 1 receptor activation in ascending aortic remodeling in response to increased biomechanical forces using a transverse aortic constriction (TAC) mouse model...
  6. pmc Recurrent gain-of-function mutation in PRKG1 causes thoracic aortic aneurysms and acute aortic dissections
    Dong Chuan Guo
    Department of Internal Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
    Am J Hum Genet 93:398-404. 2013
    ....
  7. pmc Successes and challenges of using whole exome sequencing to identify novel genes underlying an inherited predisposition for thoracic aortic aneurysms and acute aortic dissections
    Dianna M Milewicz
    Division of Medical Genetics, Department of Internal Medicine, University of Texas Health Science Center at Houston UT Health, 6431 Fannin, Suite 6 100, Houston, TX 77030, USA Electronic address
    Trends Cardiovasc Med 24:53-60. 2014
    ..Putative genes are validated by identifying additional families with a causative mutation in the genes. This approach has successfully identified novel genes for FTAAD. ..
  8. pmc Activation of MRTF-A-dependent gene expression with a small molecule promotes myofibroblast differentiation and wound healing
    Lissette S Velasquez
    Department of Medicine, Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642
    Proc Natl Acad Sci U S A 110:16850-5. 2013
    ....
  9. pmc Acute aortic dissections with pregnancy in women with ACTA2 mutations
    Ellen S Regalado
    Department of Internal Medicine, University of Texas Health Science Center at Houston, Houston, Texas
    Am J Med Genet A 164:106-12. 2014
    ..Women with ACTA2 mutations who are planning to get pregnant should be counseled about this risk of aortic dissection, and proper clinical management should be initiated to reduce this risk...

Research Grants30

  1. Pulmonary Surface Liquid Homeostasis
    RICHARD CHARLES BOUCHER; Fiscal Year: 2013
    ..abstract_text> ..
  2. Thrombus Formation and Antithrombotic Intervention
    John H Griffin; Fiscal Year: 2013
    ..New knowledge will contribute to improving prevention, diagnosis and treatment of relevant diseases related to thrombosis. ..
  3. Immune Responses To AAV-Mediated FIX Gene Transfer
    Hildegund C J Ertl; Fiscal Year: 2013
    ..HC ErtI): T Cells to AAV and AAV-Encoded Transgene Products Project 3 (RW Herzog, C Terliorst): Pathways Towards Immune Tolerance to Coagulation Factors Core A (HC ErtI): Administrative Core Core B (S Zliou): Vector Core ..
  4. INNATE AND ADAPTIVE IMMUNE RESPONSES IN TH2-HIGH ASTHMA
    John V Fahy; Fiscal Year: 2013
    ..Including studies in human biospecimens in a PPG that promises to advance understanding of airway TH2 inflammation in ways that are highly relevant to patients with asthma. ..
  5. UNMC EPPLEY CANCER CENTER SUPPORT GRANT
    Kenneth H Cowan; Fiscal Year: 2013
    ....
  6. Cardiac Myosin Binding Protein-C: Structure, Function, and Regulation
    David M Warshaw; Fiscal Year: 2013
    ..abstract_text> ..
  7. Pacific NorthWest Regional Center of Excellence (PNWRCE)
    Jay A Nelson; Fiscal Year: 2013
    ..pseudomallei host pathogen response during both the septicemic as well as the intracellular phases of the disease. ..
  8. Digitalis-Induced Signaling by Cardiac Na+/K+-ATPase
    Amir Askari; Fiscal Year: 2013
    ..abstract_text> ..
  9. Pacific Southwest RCE for Biodefense &Emerging Infectious Diseases Research
    Alan G Barbour; Fiscal Year: 2013
    ..abstract_text> ..
  10. Rocky Mountain Regional Center of Excellence or Biodefense and Emerging Infectiou
    John T Belisle; Fiscal Year: 2013
    ..abstract_text> ..
  11. INTEGRATED MECHANISMS OF CARDIAC MALADAPTATION
    R John Solaro; Fiscal Year: 2013
    ..Studies proposed here offer the potential for novel diagnostic procedures early in the progression of the disorders, and targets for novel therapies. (End of Abstract) ..