Lessons on the pathogenesis of aneurysm from heritable conditions

Abstract

Aortic aneurysm is common, accounting for 1-2% of all deaths in industrialized countries. Early theories of the causes of human aneurysm mostly focused on inherited or acquired defects in components of the extracellular matrix in the aorta. Although several mutations in the genes encoding extracellular matrix proteins have been recognized, more recent discoveries have shown important perturbations in cytokine signalling cascades and intracellular components of the smooth muscle contractile apparatus. The modelling of single-gene heritable aneurysm disorders in mice has shown unexpected involvement of the transforming growth factor-β cytokine pathway in aortic aneurysm, highlighting the potential for new therapeutic strategies.

Figure 1. Sites of TAA in transforming growth factor-β vasculopathy syndromes

Multidetector computer tomographic reconstruction images are shown. a, The thoracic aorta of a 9-year-old patient with Loeys-Dietz syndrome (LDS) is shown after emergent repair of a proximal descending (Stanford type B) aortic dissection, with a large unrepaired aortic root aneurysm (yellow arrowhead). The red arrowhead denotes the dacron tube graft. b, The thoracic aorta of a 16-year-old patient with LDS is shown after surgical repair of an aortic root aneurysm (yellow arrowhead), with a discrete fusiform aneurysm of the proximal descending aorta (red arrowhead). Bar = 3 cm.

Figure 2. The TGF-β- and angiotensin II-signalling pathways

Signalling cascades of TGF-β and angiotensin II have been implicated in the pathogenesis of aneurysm. Fibrillin-1, the major component of extracellular microfibrils, binds and sequesters the large latent complex (LLC) of TGF-β. After TGF-β activation (release), ligand binds to the TGF-β receptor and activates both canonical (grey) and non-canonical (blue) signalling cascades. The extensive cross-talk between the TGF-β and angiotensin II type 1 receptor (AT1R) signalling pathways is indicated. Key terminal events in the pathogenesis of aneurysm may include MMP-mediated proteolysis, CTGF-mediated epithelial-to-mesenchymal transition and tissue remodelling, or IL-6- and MCP-1-mediated inflammation. Proteins indicated in purple have been directly implicated in human hereditary aneurysmal disease (see Table 1). α-SMA, α-smooth muscle actin; MEK1, MAP kinase kinase 1; MLCK, myosin light chain kinase; MLCP, myosin light chain phosphatase; p190 RhoGAP, Rho GTPase-activating protein 5; SHP2, protein-tyrosine phosphatase 2C; TAK1, mitogen-activated protein kinase kinase kinase 7 (also known as TAK1); MEK1, MAP kinase kinase 1; MLCK, myosin light chain kinase; MLCP, myosin light chain phosphatase; p190 RhoGAP, Rho GTPase-activating protein 5; SHP2, protein tyrosine phosphatase 2C; α-SMA, α-smooth muscle actin.

Figure 3. TGF-β signalling in heritable aneurysm syndromes

The proposed mechanisms for the amplification of TGF-β signalling in conditions such as LDS are shown. a, Potential cell-autonomous mechanism of upregulation of TGF-β signalling in LDS. TGF-β ligand usually stimulates canonical and non-canonical pathways (left), with canonical signalling providing feedback inhibition. In LDS (right), TGF-β receptor kinase domain mutations (depicted in green) may cause a selective decrease in canonical signalling and thus in feedback inhibition. Cell-autonomous compensation (that is, increased ligand expression and activation) to maintain canonical signalling would result in excessive activation of non-canonical signalling cascades. b, The TGF-β cancer paradox. During the progression of tumorigenesis, tumour cells often lose TGF-β responsiveness as a method of escaping TGF-β-mediated cell-cycle arrest. A lack of feedback inhibition results in upregulation of TGF-β expression by tumour cells and excessive activation of neighbouring signalling-competent stromal cells, which promotes angiogenesis and tumour invasion. c, Potential non-cell-autonomous mechanism of upregulation of TGF-β signalling in vascular disease. Sites of developmental field boundaries correspond anatomically to sites of predisposition for aneurysm in TGF-β vasculopathy syndromes (the aortic and pulmonary roots, the juxtaductal aorta and the suprarenal abdominal aorta). Inset shows cellular events thought to occur at the transition between second heart field (brown)- and cardiac neural crest (green)-derived VSMCs. A relative perturbation of TGF-β signalling would have a disproportionate effect on the more vulnerable lineage (second heart field), resulting in increased ligand expression and excessive TGF-β signalling by adjacent cells of a different lineage (cardiac neural crest) with relative preservation of signalling potential.

Figure 4. TGF-β signalling in LDS aorta

Immunohistochemical staining for nuclear pSMAD2 (a marker of TGF-β signalling) in the aortic root of a control individual and a patient with LDS. An enlarged view of the LDS aorta is shown on the right. Although TGF-β signalling is markedly increased in LDS, two distinct cell populations are observed in the aortic media, with either absent (blue nuclei) or strongly positive (brown nuclei) activity. The low-power images represent a montage of images taken at 10× magnification to span the entire thickness of the aortic wall. The image on the right is shown at 60× magnification.