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 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 (RLC) 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 de-phosphorylation of the RLC, and predisposes to thoracic aortic disease. Furthermore, SMCs cannot generate force without connections to the extracellular matrix (ECM) through focal adhesions, and mutations in the major protein in the ECM, 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.

Therapeutics Targeting Drivers of Thoracic Aortic Aneurysms and Acute Aortic Dissections: Insights from Predisposing Genes and Mouse Models

“…Additional familial TAAD genes have been identified that encode proteins involved in the structural elements and kinases controlling SMC contraction (33). We determined that the most frequently altered familial TAAD gene is ACTA2 , which encodes the SMC-specific isoform of α -actin (SM α -actin) (34).…”

Heritable Thoracic Aortic Disease Genes in Sporadic Aortic Dissection

“…Pathogenic variants in 11 genes confer a highly penetrant, dominantly inherited risk for aortic aneurysms and dissections with or without syndromic features (e.g., Marfan syndrome), termed heritable thoracic aortic disease (HTAD), and include ACTA2 , COL3A1 , FBN1 , LOX , MYH11 , MYLK , PRKG1 , SMAD3 , TGFB2 , TGFBR1 , and TGFBR2 (1). …”

Vascular disease-causing mutation, smooth muscle α-actin R258C, dominantly suppresses functions of α-actin in human patient fibroblasts

“…Dissected aortas exhibit characteristic features, including loss and disarray of smooth muscle cells in the medial layer, loss of elastic fibers, and proteoglycan accumulation in the medial space (4). These observations have led to the hypothesis that TAADs arise because of inappropriate mechanosensing and mechanoregulation of the extracellular matrix by aortic smooth muscle cells (5,14,15). Such deficits are believed to make the aortic wall vulnerable to dilation and dissection.…”