Aneurysms are permanent, localized dilatations of an artery greater than 50% of the normal diameter. They progressively dilate while remaining mostly asymptomatic until a life-threatening rupture and/or dissection occurs. Prophylactic surgical repair remains the only proven method to prevent risk of death caused by mechanical failure of the vessel. Aneurysms can develop both in the thoracic and abdominal aorta. Aneurysms that affect the abdominal aorta are more common, tend to occur in older individuals, and have no known monogenic cause, although multiple candidate risk loci have been reported.
While less common, thoracic aortic aneurysms (TAA) can develop in the absence of cardiovascular risk factors, affect younger individuals, and have a higher degree of heritability. Although a hereditary predisposition to TAA confers an increased risk of aortopathy to all segments of the vessel, pathogenic mechanisms can differ depending on the specific aortic location. For example, dissections of the thoracic descending aorta can occur even when dilation is limited or absent and as a complication of proximal aortic repair.
Structure and Features of the Normal Aortic Wall
The healthy arterial wall is composed of three distinct layers: the tunica intima, the tunica media, and the tunica adventitia. The primary cellular component of the tunica intima is endothelial cells, which are arranged in a monolayer directly facing the lumen of the vessel. Endothelial cells are anchored to a basement membrane of collagen, laminin, and proteoglycans and provide a semi-selective, flexible barrier that responds to shear stress, modulates immune responses, and participates in vascular repair. The subendothelial matrix, which in larger animals can include intimal smooth muscle cells, is separated from the next outer layer by the internal elastic lamina.
Modulation of Medial VSMC Phenotype
Analysis of aneurysmal tissue obtained from both patients and mouse models reveals common end-point characteristics that are observed regardless of etiology. Although both the intimal and adventitial layers participate in the disease process, the progressive mechanical weakening of the vessel is caused by the “degeneration” of the tunica media. Features associated with medial degeneration include fragmentation of elastic lamellae, increased and/or abnormal deposition of collagen and proteoglycans, and increased wall permeability. Although glycosaminoglycan and proteoglycans serve important physiological functions and help elastic lamellae resist hemodynamic forces, the accumulation of these molecules in TAA, either by increased deposition or decreased degradation, obstructs elastic fibers, increases the swelling pressures on the vessel wall, and has been strongly associated with aortic dissection and rupture in a mouse model of MFS.
Genes Associated with Syndromic and Non-Syndromic Hereditary Thoracic Aortic Aneurysm
The identification of genetic variants that cause hereditary forms of aneurysm provides the opportunity to clearly define the molecular deficiencies that initiate this disease. Several recent reviews have summarized the current list of approximately 30 genes involved in the development of either syndromic or non-syndromic forms of TAA. Although criteria for inclusion vary, 11 genes are currently confirmed as “definitive” determinants of highly penetrant TAA based on the Clinical Genome Resource framework. Despite this progress, a causative mutation is found in only approximately 30% of patients with a clear positive family history, suggesting that causative mutations in genes not currently tested in familial cases of TAA remain to be identified.
Proposed Model of TAA Pathogenesis Based on the Function of Known Causal Variants
The discovery of mutations that cause hereditary forms of TAA has identified fundamental cellular and molecular process that are necessary to retain VSMC homeostasis and prevent medial degeneration. The preponderance of evidence supports a model whereby a defective assembly of connections between the ECM and VSMCs initiates the phenotypic transition of these cells from a quiescent, contractile phenotype to one that is highly synthetic and conducive to proteolytic degradation of the ECM.
Adaptive and Maladaptive Responses in TAA: Implications for Therapy
We have a limited understanding of the compensatory mechanisms activated in response to germline TAA-associated mutations. Feedback responses attempting to offset the negative consequences of a given genetic variant are active throughout prenatal and postnatal development and might significantly modify the structural, cellular, and molecular properties of the adult aorta.
Integrity of the aorta is maintained by a complex and dynamic network of mechanical and biochemical signals. Genetic variants that cause hereditary aneurysm disorders affect the ability of VSMCs to receive and interpret these signals, resulting in phenotypic modulation in these cells and maladaptive remodeling of the ECM, eventually leading to mechanical failure of the vessel wall. Delineation of the molecular functions affected by TAA-associated mutations has identified molecular deficiencies that initiate the pathogenic process. These include defects in components of the elastin-contractile unit and positive effectors of canonical TGF-β signaling. The mechanisms by which these primary deficiencies interact with other pathways regulating VSMC homeostasis to produce both adaptive and maladaptive outcomes is the subject of current investigation. Although current therapeutic strategies focus on reducing mechanical stress, the identification of adverse signaling events that participate in maladaptive responses to the primary genetic insult may offer new therapeutic opportunities.