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Review
. 2017 Mar;54(3):95-155.
doi: 10.1067/j.cpsurg.2017.01.001. Epub 2017 Feb 3.

Molecular pathogenesis of genetic and sporadic aortic aneurysms and dissections

Ying H Shen  1 , Scott A LeMaire  2
Affiliations
Review

Molecular pathogenesis of genetic and sporadic aortic aneurysms and dissections

Ying H Shen et al. Curr Probl Surg. 2017 Mar.
No abstract available

PubMed Disclaimer

Figures

Fig. 1.
Fig. 1.
Aortic segments. The aorta comprises the ascending thoracic aorta, aortic arch, descending thoracic aorta, suprarenal aorta, and infrarenal aorta. The diaphragm divides the aorta into the thoracic and abdominal aorta. (Color version of figure is available online.)
Fig. 2.
Fig. 2.
Aortic aneurysms and dissections. (A) Aortic aneurysm occurs when the progressive weakening of the aortic wall causes the aorta to enlarge to a diameter of at least 1.5 times greater than normal. (B) Aortic dissection occurs when a tear forms within the aortic wall and causes blood to flow between the layers, thereby creating a false lumen. (Color version of figure is available online.)
Fig. 3.
Fig. 3.
Structure of the aortic wall. (A) The aortic wall is composed of a thin inner layer (the intima), a thick medial layer (the media), and a thin outer layer (the tunica adventitia). (B) The lamellar unit is composed of smooth muscle cells (SMCs) sandwiched between 2 layers of elastic fibers and surrounded by collagen bundles. (Color version of figure is available online.)
Fig. 4.
Fig. 4.
The elastin-contractile unit and mutations affecting aortic contractile function. The elastin-contractile unit is a unique configuration of elastic fibers, focal adhesions or dense plaques in the membrane, and contractile filaments inside the SMCs. The elastic fibers are organized as a core of elastin surrounded by microfibrils that are composed of fibrillin, microfibril-associated glycoproteins (MAGPs), elastin microfibril interfacer protein 1 (EMILIN1), fibulins, and other glycoproteins. An SMC contractile unit is composed of actin-containing thin filaments and myosin-containing thick filaments, along with regulatory proteins. Mechanical stimuli are transmitted from the elastic fiber, through the focal adhesions or dense plaques in the membrane, through the anchoring proteins or actin linkage proteins, and to the contractile unit, leading to the activation of SMC contraction. Genetic thoracic aortic aneurysms and dissections (TAAD) are associated with mutations in genes encoding proteins that control the structure and function of the elastin-contractile unit. These proteins include SM α-actin, myosin heavy chain 11 (MYH11), myosin light chain kinase (MYLK), filamin A, fibrillin-1, microfibril-associated glycoprotein 2 (MAGP2), EMILIN1, and lysyl oxidase (LOX). (Color version of figure is available online.)
Fig. 5.
Fig. 5.
Transforming growth factor β (TGF-β) signaling in aortic aneurysms and dissections (AAD). TGF-β ligands are produced as a large latent TGF-β complex consisting of mature TGF-β, latency-associated peptide (LAP), and a latent TGF-β-binding protein (LTBP). TGF-β activates canonical and noncanonical signaling pathways. In the canonical pathway, TGF-β binds and induces heteromeric complex formation between TGF-β type (TβRI) and type II (TβRII) receptors, leading to TβRI phosphorylation. TβRI, in turn, phosphorylates and activates downstream transcription factors such as SMADs (ie, R-SMADs, SMAD2, and SMAD3). SMADs translocate to the nucleus, where they bind to the promoters of target genes and transactivate their gene expression. The canonical TGF-β signaling pathway promotes aortic development and maintains aortic wall homeostasis. Mutations in genes encoding TGF-β ligands, receptors, and downstream transcription factor SMAD cause TAAD. In the noncanonical pathways, the activated TGF-β receptor complex transmits signals through other pathways, such as TGF-β-activated kinase 1 (TAK1), p38 mitogen-activated protein kinase (p38 MAPK), extracellular signal-regulated kinase (ERK), JUN N-terminal kinase (JNK), and nuclear factor-κB (NF-κB). The noncanonical TGF-β pathways promote aortic destruction and AAD development. (Color version of figure is available online.)
Fig. 6.
Fig. 6.
Common pathologic changes in aortic aneurysms and dissections (AAD). The common pathologic features of AAD are aortic degeneration, which is characterized by aortic smooth muscle cell (SMC) death and loss; elastic fiber destruction and depletion; and aortic inflammation. Aortic degeneration weakens the aortic wall, leading to the development of aortic aneurysm, dissection, and rupture. (Color version of figure is available online.)
Fig. 7.
Fig. 7.
Smooth muscle cell (SMC) phenotype changes in aortic aneurysms and dissections (AAD). SMCs possess remarkable plasticity. Differentiated SMCs express SMC-specific contractile proteins and have characteristic myocyte morphology and contractile properties. In differentiated contractile SMCs, transcription factors myocardin and serum response factor (SRF) bind to the CArG motif in the promoters of SMC genes and induce the expression of SMC-specific contractile proteins. Under conditions such as inflammation and injury, SMCs can lose their contractile phenotype and exhibit phenotypes resembling those of inflammatory cells, fibroblasts, or osteogenic cells–a phenomenon termed phenotypic switching. In dedifferentiated SMCs, transcription factors such as Krupple-like factor 4 (KLF4) inhibit myocardin or SRF-mediated SMC gene expression, thereby inducing SMC phenotype alterations. Several pathways such as those involving angiotensin II (Ang II), transforming growth factor β (TGF-β), connective tissue growth factor (CTGF), platelet-derived growth factor (PDGF), interleukin 6 (IL-6), and reactive oxygen species (ROS) have a role in promoting the SMC phenotype switch. (Color version of figure is available online.)
Fig. 8.
Fig. 8.
Inflammatory cells in aortic aneurysms and dissections (AAD). In AAD, a variety of inflammatory cells accumulates, including lymphocytes, macrophages, mast cells, and neutrophils. Inflammatory cells actively participate in tissue injury, repair, and remodeling in AAD. After tissue injury, inflammatory cells infiltrate the aortic wall, clear tissue debris, and initiate tissue repair and regeneration. Once the tissues are repaired, inflammatory cells are removed and the inflammation is resolved. Insufficient clearance of damaged tissues, deficient tissue repair and regeneration, and impaired anti-inflammatory responses and inflammation resolution can lead to sustained inflammation with uncontrolled production of destructive inflammatory mediators and growth factors, which aggravate tissue injury and contribute to maladaptive fibrotic remodeling. (Color version of figure is available online.)
Fig. 9.
Fig. 9.
Angiotensin II signaling in aortic aneurysms and dissections (AAD). Angiotensin II (shown as Ang II) has 2 distinct receptors, AT1R and AT2R, which counter-regulate each other and have opposite effects on vascular function. The angiotensin system is critically involved in regulating the structure and function of aortic cells and in maintaining aortic homeostasis. However, excessive stimulation of angiotensin II signaling via AT1R activates several pathways involving rho or rho-associated protein kinase (ROCK), NFkB, ERK1/2, JNK, and p38 and induces NADPH oxidase activation and reactive oxygen species production. These signaling events promote aortic cell dysfunction, inflammation, and fibrotic remodeling, leading to aortic destruction and the formation and progression of AAD. (Color version of figure is available online.)
Fig. 10.
Fig. 10.
MicroRNAs (miRNAs) in aortic aneurysms and dissections (AAD). MiRNAs are small, noncoding RNAs that, by inducing mRNA degradation and translational repression, posttranscriptionally silence target mRNAs. MiRNA genes are transcribed by RNA polymerase II (Pol II). The precursor primary miRNA (pri-miRNA) is cleaved by the RNase III Drosha and DiGeorge syndrome critical region 8 (DGCR8) to form a hairpin-shaped precursor miRNA (pre-miRNA). The pre-miRNA is exported from the nucleus into the cytoplasm, where it is further cleaved by the RNase III enzyme Dicer, yielding an imperfect miRNA-miRNA* duplex. MiRNA is then incorporated into the RNA-induced silencing complex (RISC). Association of a miRNA with its mRNA targets results in degradation and translational inhibition of the target mRNAs. Stress conditions can influence miRNA biogenesis at multiple levels. Competing endogenous RNAs (ceRNAs) bind and sequester miRNAs, preventing them from binding to their mRNA targets and thereby regulating miRNA activity. Several miRNAs that target the extracellular matrix or tissue inhibitor of matrix metalloproteinase-3 (TIMP-3) have been implicated in aortic disease. lncRNA, long noncoding RNA; m7G, 7-methylguanosine (a modified form of guanosine attached to the 5’ ends of mRNAs); ORF, open reading frame. (Modified with permission from van Rooij E and Olson EN. MicroRNA therapeutics for cardiovascular disease: opportunities and obstacles. Nat Rev Drug Discov. 2012;11:860-72.) (Color version of figure is available online.)
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