Pathogenic Mechanisms of Bicuspid Aortic Valve Aortopathy

Abstract

Bicuspid aortic valve (BAV) is the most common congenital valvular defect and is associated with ascending aortic dilation (AAD) in a quarter of patients. AAD has been ascribed both to the hemodynamic consequences of normally functioning and abnormal BAV morphology, and to the effect of rare and common genetic variation upon function of the ascending aortic media. AAD manifests in two overall and sometimes overlapping phenotypes: that of aortic root aneurysm, similar to the AAD of Marfan syndrome; and that of tubular AAD, similar to the AAD seen with tricuspid aortic valves (TAVs). These aortic phenotypes appear to be independent of BAV phenotype, have different embryologic origins and have unique etiologic factors, notably, regarding the role of hemodynamic changes inherent to the BAV phenotype. Further, in contrast to Marfan syndrome, the AAD seen with BAV is infrequently present as a strongly inherited syndromic phenotype; rather, it appears to be a less-penetrant, milder phenotype. Both reduced levels of normally functioning transcriptional proteins and structurally abnormal proteins have been observed in aneurysmal aortic media. We provide evidence that aortic root AAD has a stronger genetic etiology, sometimes related to identified common non-coding fibrillin-1 (FBN1) variants and other aortic wall protein variants in patients with BAV. In patients with BAV having tubular AAD, we propose a stronger hemodynamic influence, but with pathology still based on a functional deficit of the aortic media, of genetic or epigenetic etiology. Although it is an attractive hypothesis to ascribe common mechanisms to BAV and AAD, thus far the genetic etiologies of AAD have not been associated to the genetic etiologies of BAV, notably, not including BAV variants in NOTCH1 and GATA4.

Keywords: GATA4; bicuspid aortic valve; fibrillin; genetics; thoracic aortic aneurysm; transforming growth factor-β.

Figure 1

Classification of ascending aortic dilation phenotypes. Ascending aortic dilations (aneurysms) can be classified into a tubular phenotype (A) located above the sinotubular junction (STJ) and an aortic root phenotype (B) located below the STJ. This classification is neither explanatory nor complete, as ascending aortic dilations frequently extend above or below the STJ and may extend into the aortic arch or beyond. However, it provides a functional distinction based on embryogenic origins of the aorta and surgical approaches. Copyright: Glen Oomen, M.Sc. (http://www.glenoomen.com/medical-illustration/b2mswldypmppf644fjbm1k9kc3w472)

Figure 2

The embryological origins of the thoracic vasculature and outflow tract. The embryonic first and second heart fields are derived from the lateral plate mesoderm. The first heart field forms the early heart tube, into which second heart field cells migrate to form the convoluting heart. The cardiac neural crest is derived from a clone of neural crest cells that migrate along the third and fourth pharyngeal arches to form the head and upper limb arteries along with the ascending aorta and aortic arch. The pulmonary artery is formed from neural crest cells that migrate along the sixth pharyngeal arch.

Figure 3

The embryological origins of smooth muscle cells of the aorta. The adult aortic root is principally derived from the second heart field (yellow), whereas the ascending aorta and arch are derived from the cardiac neural crest (blue) and the descending aorta is derived from the paraxial mesoderm (green). In the adult aorta, smooth muscle cells of both the second heart field and neural crest form the aortic root and ascending aorta, while the descending aorta below the ductus arteriosus is composed of cells from the lateral mesoderm. CNC, cardiac neural crest; SHF, second heart field; PAM, paraxial mesoderm.

Figure 4

The embryological origins of smooth muscle cells of the aortic valve. Embryonic development of the aorta valve incorporates smooth muscle cells derived from both the second heart field and cardiac neural crest. Although, portrayed as two layers of distinct cellular origins with cardiac neural crest-derived cells occupying the fibrosal side (left side of each figure) of the valve and second heart field-derived cells occupying the ventricular side of the valve (left side of each figure), there is evidence for endocardial-to-mesenchymal transformation in the endocardial cushions that develop into the valve, along with considerable plasticity of all elements of the developing valve.

Figure 5

The embryological destinations of the intrathoracic vasculature. Development of the upper body arterial tree is predicated on expansion, migration, and apoptosis of cell populations in the branchial arteries to yield its neonatal structure. The branchial arteries are numbered 1–6.

Figure 6

Structure of the ascending aortic media. The media of the aortic wall is composed of vascular smooth muscle cells (SMCs) and an extracellular matrix (ECM) of elastic fibers, collagen fibers, and proteoglycans. Elastic fibers are the major ECM component and provide extensibility to the aortic wall. Cross-linking of tropoelastin monomers by lysyl oxidase (LOX) forms elastin molecules, which in turn cross-link with microfibrils to form elastic fibers. Microfibrils are composed of fibrillin and several microfibril-associated proteins (MFAPs), such as elastin microfibril interface-located protein 1 (EMILIN-1), microfibril-associated glycoproteins (MAGP-1 and -2), and fibulins. Notably, microfibrils provide a substrate for the large latent complex and transforming growth factor-β sequestration. Modified from Wu et al. (2013).

Figure 7

Structural and functional roles of fibrillin in the extracellular matrix. Fibrillin microfibrils associate with elastin to form elastic fibers in the aortic media (see Figure 2). Key functional roles are (i) binding to elastin via the fibulins and other extracellular matrix (ECM) glycoproteins; (ii) sequestering transforming growth factor-β (TGF-β) via the large latent complex, bone morphogenetic protein (BMP) and growth and differentiation factors (GDFs); and (iii) linking to smooth muscle cells of the media via integrins. Modified from Robertson et al. (2011).

Figure 8

Schematic of a mechanistic approach to the development of thoracic ascending aortic dilation (AAD) ultimately leading to aneurysm. This schematic assumes three groups of AAD etiologic factors: genes causing a bicuspid aortic valve (BAV) that may also be causing AAD; genes causing AAD but not BAV; and hemodynamic factors that contribute to AAD.

Figure 9

Plasticity of smooth muscle cell phenotype. The spectrum of smooth muscle cell (SMC) phenotype from proliferative to contractile phenotypes is dependent upon signaling from multiple sources. The sources include adjacent SMCs and vascular endothelial cells, mediated by cell-cell interaction and soluble factors including transforming growth factor-β (TGF-β), laminin, fibroblast growth factor, platelet derived growth factor, epidermal growth factor, and angiotensin II, amongst others. Mechanical signaling via the extracellular matrix, cell-cell mechanical sensing, and the intracellular cytoskeleton and primary cilium are propagated through the intracellular dense plaques. These signals yield changes in cytoskeletal architecture and drive plasticity across the spectrum of SMC phenotype.

Figure 10

Activation of the transforming growth factor-β (TGF-β) signaling pathway leading to a smooth muscle cell contractile phenotype. Members of the TGF-β superfamily that include TGF-βs, bone morphogenetic proteins (BMPs), and growth and differentiation factors (GDFs) have similar functional properties regulating cell growth, differentiation, apoptosis, and extracellular matrix synthesis in vascular smooth muscle cells (SMCs). TGF-β ligands are synthesized as latent precursor molecules (LTGF-β), which are activated via proteolytic cleavage. Active TGF-β signaling is transmitted through two types of transmembrane serine/threonine protein kinase receptors: TGF-β type I (TGFβRI) and principally type II (TGFβRII) and mediated by a sequence of phosphorylated Smad proteins. In addition to the canonical Smad signaling pathway that directly regulates the transcription of Smad-dependent target genes, TGF-β function can also be mediated by Smad-independent pathways including MAPK signaling pathways, such as p38 MAPK and c-Jun NH2-terminal kinase, phosphatidylinositol 3-kinase/Akt pathway, and Wnt signaling. TGF-β signaling via TGFβRII plays a pivotal role in both second heart field and cardiac neural crest derived SMC phenotype differentiation during vascular development as well as SMC phenotypic switching in disease states. TGF-β signaling induces SMCs to change shape into elongated SMC shape accompanied by an up-regulation of SMC contractile proteins.