Altered Smooth Muscle Cell Force Generation as a Driver of Thoracic Aortic Aneurysms and Dissections

Arterioscler Thromb Vasc Biol. 2017 Jan;37(1):26-34. doi: 10.1161/ATVBAHA.116.303229. Epub 2016 Nov 22.


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.

Keywords: Marfan syndrome; aortic aneurysm; aortic dissection; mutation; thoracic aorta; vascular smooth muscle cells.

Publication types

  • Review
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / genetics
  • Actins / metabolism
  • Aneurysm, Dissecting / genetics
  • Aneurysm, Dissecting / metabolism
  • Aneurysm, Dissecting / pathology
  • Aneurysm, Dissecting / physiopathology*
  • Animals
  • Aortic Aneurysm, Thoracic / genetics
  • Aortic Aneurysm, Thoracic / metabolism
  • Aortic Aneurysm, Thoracic / pathology
  • Aortic Aneurysm, Thoracic / physiopathology*
  • Calcium-Binding Proteins / genetics
  • Calcium-Binding Proteins / metabolism
  • Cyclic GMP-Dependent Protein Kinase Type I / genetics
  • Cyclic GMP-Dependent Protein Kinase Type I / metabolism
  • Dilatation, Pathologic
  • Elastin / metabolism
  • Genetic Markers
  • Genetic Testing
  • Heredity
  • Humans
  • Mechanotransduction, Cellular
  • Muscle, Smooth, Vascular / metabolism
  • Muscle, Smooth, Vascular / pathology
  • Muscle, Smooth, Vascular / physiopathology*
  • Mutation
  • Myocytes, Smooth Muscle / metabolism
  • Myocytes, Smooth Muscle / pathology
  • Myosin Heavy Chains / genetics
  • Myosin Heavy Chains / metabolism
  • Myosin-Light-Chain Kinase / genetics
  • Myosin-Light-Chain Kinase / metabolism
  • Phenotype
  • Pulsatile Flow
  • Vasoconstriction* / genetics


  • ACTA2 protein, human
  • Actins
  • Calcium-Binding Proteins
  • Genetic Markers
  • MYH11 protein, human
  • Elastin
  • Cyclic GMP-Dependent Protein Kinase Type I
  • PRKG1 protein, human
  • MYLK protein, human
  • Myosin-Light-Chain Kinase
  • Myosin Heavy Chains