Pathobiology of Aortic Aneurysms

Aortic aneurysms (AAs) can develop in either the thoracic or the abdominal aorta, termed thoracic aortic aneurysm (TAA) ( Fig. 7.1 ) or abdominal aortic aneurysm (AAA) ( Fig. 7.2 ), respectively. AAs are further subclassified according to their specific location in the thoracic (ascending aorta, aortic arch, descending aorta) or abdominal (suprarenal or infrarenal) aortic segments ( Fig. 7.3 ). Although this classification may appear purely descriptive at first glance, it is important to note that TAA and AAA generally represent quite distinct diseases with heterogeneous etiology.

AAs due to genetic disorders with single-gene mutations, as seen in syndromic connective tissue disorders (e.g., Marfan syndrome or Loeys-Dietz syndrome), primarily affect the ascending aorta, and, less often, the descending and abdominal segments. In addition, less common aortopathies, including inflammatory vasculitides (e.g., Takayasu arteritis, giant cell arteritis) and chronic infections such as tertiary syphilis, typically affect thoracic segments. In contrast, age-related, degenerative (sporadic) AAs primarily occur in the descending aorta and are most frequently observed in the form of infrarenal AAAs. These have historically been considered as a manifestation of atherosclerosis but—as increasing epidemiological and pathomechanistic evidence suggests—may, in fact, represent a distinct disease.

The differential susceptibility of specific aortic segments to different etiological factors may partly be explained by embryological, as well as structural, aspects. Embryologically, the aorta is composed of cells originating from the neural crest, mesenchyme, and splanchnic mesoderm (see Fig. 7.3 ). Primitive arteries are surrounded by smooth muscle cells (SMCs) of mesodermal origin; however, during later development, the primitive SMCs of the ascending thoracic aorta are replaced in part by SMCs that migrate from the neural crest. These neural crest-derived SMCs exhibit distinctive biology compared with mesodermal SMCs, particularly regarding their response to stimulation with cytokines/growth factors, such as transforming growth factor-β (TGFβ). Moreover, neural crest–derived SMCs lead to adaptive remodeling of the thoracic aorta, producing more elastic lamellae during development and growth. Structurally, this results in significantly higher elastin content of the thoracic aorta compared with the abdominal segment, leading to greater mechanical distensibility and buffering cyclical mechanical stress from pulsatile cardiac action (aortic Windkessel function). In contrast, the lower elastin content of the abdominal aorta may render this segment particularly susceptible to age-related stiffening and degenerative aneurysm formation (see Biomechanical Stress). Despite the variety of etiologies and triggers underlying human AA, and the noted spatial tendencies, AAs to a variable extent exhibit common pathobiological and mechanistic features, including degradation of the medial extracellular matrix (ECM proteolysis), smooth muscle phenotypic switching, and apoptosis, as well as inflammation and oxidative stress ( Fig. 7.4 ).

Degradation of the medial extracellular matrix

Remodeling and destruction of elastin and collagen fibers, the two major mechanical load-bearing components of the aortic ECM, are a hallmark of AA disease. Medial elastin and interstitial collagen (types I and III) determine much of the structural integrity and stability of arteries. The mechanistic importance of ECM breakdown, and elastin fragmentation in particular, for AA pathogenesis has been made apparent in a variety of animal models where local treatment of previously intact aortic segments with elastolytic agents (such as porcine pancreatic elastase or calcium chloride) results in subsequent aneurysm development.

One critical mechanism leading to increased ECM proteolysis is an imbalance between matrix-degrading matrix metalloproteinases (MMPs) and their endogenous antagonists, the tissue inhibitors of metalloproteinases (TIMPs). MMPs are divided into subclasses based upon substrate specificity and include gelatinases, elastases, and collagenases. Members of the gelatinase subclass (MMP-2 and MMP-9) degrade denatured fibrillar collagen (gelatin), elastin, and native collagen types IV, V, and VII, along with other ECM components, and are thought to be of particular importance in AA. MMP-2 (gelatinase A) is constitutively expressed by SMCs. MMP-9 (gelatinase B) can be produced by macrophages, fibroblasts, or SMCs with a secretory phenotype. MMP-2 and MMP-9 have been extensively studied in both TAA and AAA. Expression and activity of MMP-2 and MMP-9 are increased in human AAA, and gene knockout of these enzymes abolishes experimental AAA formation. Similarly, MMP-9 levels are increased in human TAA, and MMP-9 knockdown is protective in preclinical TAA models. (The significance of MMP-2 in TAA pathogenesis is less clear.) Regarding the role of TIMPs, there is no consistent evidence that TIMP levels are altered in aneurysmal compared with healthy aortic tissue. As such, TIMP dysregulation alone may not serve as a causative factor for AA; however, a multitude of animal studies indicate that manipulation of TIMP activity clearly affects AA progression, suggesting that altered MMP/TIMP balance influences aneurysmal disease. Notably, therapeutic strategies that focus on MMP inhibition (e.g., the use of doxycycline or roxithromycin for MMP-9 inhibition) have not thus far translated into attenuated AAA growth in humans. The expression of serine proteases (such as tissue-type plasminogen activator [t-PA], urokinase-type plasminogen activator [u-PA], and plasmin) that may activate MMPs, as well as cysteine proteases that exhibit potent elastolytic activity (e.g., cathepsins S and K), is also increased in AA.

Smooth muscle dysregulation

A common thread that links the pathobiology of nearly all arterial diseases is the progressive dysfunction of mural SMCs. During AA formation, aortic SMCs manifest phenotypic switching away from their relatively quiescent contractile form and toward a proliferative, migratory, and secretory phenotype with proinflammatory characteristics. Later in AA development, SMC dropout due to apoptosis predominates, which leads to mural weakening, progressive expansion, and ultimately dissection or rupture. Degradation of the mural ECM framework surrounding aortic SMCs breaks cell-matrix contacts, triggering phenotypic switching. In addition, the local inflammatory milieu found in AA encourages SMC dedifferentiation.

Genetically, aneurysmal aortopathies (typically in thoracic aortic segments) may occur as a consequence of heritable, single-gene smooth muscle cell protein mutations leading to abnormal function or signaling, or premature breakdown. These include both structural elements of the SMC contractile apparatus (e.g., smooth muscle alpha-actin [ACTA2], or smooth muscle myosin heavy chain [MYH11]), as well as signaling molecules that regulate SMC tone (e.g., myosin light chain kinase [MYLK], or type I cyclic guanosine monophosphate [cGMP]-dependent protein kinase [PRKG1]).

As noted previously, a key element of AA formation involves TGFβ signaling. SMC responses to TGFβ can vary depending on growth factor subtype and embryological SMC origin. The role of TGFβ in AA formation is somewhat controversial, because decreased canonical signaling is thought to drive TAA formation, whereas, at the same time, the disease has been attributed to TGFβ hyperactivity. Inactivating mutations in TGFβ receptors and in TGFβ subtypes lead to several syndromic conditions featuring AA. Recent work has suggested that in heritable disease, the underlying aortic wall structure develops improperly, and it is the SMC response to hemodynamic load that leads to aneurysm formation, with TGFβ overactivity acting as a secondary, ineffective corrective response.

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