Hereditary Influence in Thoracic Aortic Aneurysm and Dissection

Abstract

Thoracic aortic aneurysm is a potentially life-threatening condition in that it places patients at risk for aortic dissection or rupture. However, our modern understanding of the pathogenesis of thoracic aortic aneurysm is quite limited. A genetic predisposition to thoracic aortic aneurysm has been established, and gene discovery in affected families has identified several major categories of gene alterations. The first involves mutations in genes encoding various components of the transforming growth factor beta (TGF-β) signaling cascade (FBN1, TGFBR1, TGFBR2, TGFB2, TGFB3, SMAD2, SMAD3 and SKI), and these conditions are known collectively as the TGF-β vasculopathies. The second set of genes encode components of the smooth muscle contractile apparatus (ACTA2, MYH11, MYLK, and PRKG1), a group called the smooth muscle contraction vasculopathies. Mechanistic hypotheses based on these discoveries have shaped rational therapies, some of which are under clinical evaluation. This review discusses published data on genes involved in thoracic aortic aneurysm and attempts to explain divergent hypotheses of aneurysm origin.

Keywords: Marfan syndrome; aorta; aortic disease.

Figure 1

Phenotypes of age-matched TGFβV and SMCV patients. (A, left) Aortic root aneurysm (3.5 cm, Z score = 6.2) in a patient with FBN1 mutation and MFS; (right) ascending aortic aneurysm (3.2 cm, Z score = 5.7) in a patient with ACTA2R179H mutation. (B, left) Normal pupillary width in MFS patient; (right) congenital mydriasis in patient with ACTA2 mutation. (C, left) Typical arachnodactyly seen with MFS versus (right) normal skeletal phenotype in ACTA2 mutation

Figure 2

Cellular Phenotypes in Genetically-Triggered TAA (A.) Gene products affected by genetic perturbation in TGFβVs delineate the major components of the canonical TGFβ signaling cascade (Leftward Cell). Activation of the TGF-β receptor by the ligand TGF-β2 or TGF-β3 causes receptor-mediated phosphorylation of the proteins SMAD2 and SMAD3. Phospho-SMAD2/3 bind the co-SMAD, SMAD4, and translocate to the nucleus where they bind DNA and direct transcriptional events. The activity of the SMAD proteins can be inhibited by the protein, SKI. SCMV genes affect multiple proteins involved in smooth muscle cell contraction (Rightward Cell). Myosin light chain kinase (MLCK) phosphorylates myosin light chain (MLC) and phospho-MLC allows interaction of smooth muscle myosin (smMHC) with actin isoforms, such as alpha-smooth muscle actin (α-SMC). The type 1, cGMP-dependent protein kinase (PKG-1) inhibits the activity of myosin light chain phosphatase (MLCP) that negatively regulates MLC phosphorylation. (B.) Healthy VSMCs (Leftward Cell) demonstrate stable association with the extracellular matrix through matrix binding receptors, a highly developed cytoskeletal network, and restrained biosynthetic capacity. Convergent phenotypes of VSMCs in TGFβVs and SMCVs (Rightward Cell) include loss of matrix adhesion structures with disorganized and delocalized actin cytoskeleton, hypertrophy of endoplasmic reticulum and activation of matrix degrading enzymes. Multiple signaling pathways are activated in aneurysm including TGFβ receptor signaling, angiotensin II receptor signaling receptor (AT2R), insulin-like growth factor receptor (IGF-1R) signaling, and platelet-derived growth factor receptor (PDGFR) signaling. The resultant expression and elaboration of matrix degrading enzymes with degradation of extracellular matrix components compromise the structural integrity of the aortic media, resulting in the end phenotype of aneurysm.

Figure 3

Loss of Cytoskeletal Structure in Thoracic Aortic Aneurysm Tissue. TAA stained with Verhoeff-Van Gieson (VVG) stain demonstrates familiar elastin fiber paucity and fragmentation (Upper panels). Staining of aortic tissue for filamentous actin (F-Actin) shows a nearly complete loss of intracellular organized cytoskeletal architecture in TAA (Lower panels).