Abstract
Understanding and unraveling the pathophysiology of thoracic aortic aneurysm (TAA), a vascular disease with a potentially high-mortality rate, is one of the next frontiers in vascular biology. The processes leading to the formation of TAA, of unknown cause, so-called degenerative TAA, are complex. This review advances the concept of promoters and inhibitors of the development of degenerative TAA. Promoters of TAA development include age, blood pressure elevation, increased pulse pressure, neurohumeral factors increasing blood pressure, inflammation specifically IFN-γ, IL-1 β, IL-6, TNF-α, and S100 A12; the coagulation system specifically plasmin, platelets, and thrombin as well as matrix metalloproteinases (MMPs). SMAD-2 signaling and specific microRNAs modulate TAA development. The major inhibitors or factors opposing TAA development are the constituents of the aortic wall (elastic lamellae, collagen, fibulins, fibronectin, proteoglycans, and vascular smooth muscle cells), which maintain normal aortic dimensions in the face of aortic wall stress, specific tissue MMP inhibitors, plasminogen activator inhibitor-1, protease nexin-1, and Syndecans. Increases in promoters and reductions in inhibitors expand the thoracic aorta leading to TAA formation.
Highlights
S100A12 S100A12, a pro-inflammatory protein that activates the receptor for advanced glycation end products (RAGE), is increased in 25% of thoracic aortic aneurysm (TAA) [59]
TGF-β has the potential to produce smooth muscle cell apoptosis and stimulate the differentiation of fibroblasts into myofibroblasts, which can aid in TAA formation but it can down regulate the activity of matrix metalloproteinases (MMPs), which might reduce TAA development
The loss of elastin may increase blood pressure leading to a further increase in circumferential stress, which creates a further impetus for aortic aneurysm expansion
Summary
The major component of the media of the thoracic aorta is dozens of layers of “lamellar units” consisting’s of two elastic lamellae and intervening tissue that are oriented in concentric layers around the lumen [4, 5]. The lamellae are interconnected by a network of small elastic and collagen fibers as well as proteoglycans [6]. Smooth muscle cells are in contact with fibrillin-1- and type VI collagen-containing as well as bundles of microfibrils (oxytalan fibers) [5]. Smooth muscle cells of the media have a basal laminalike layer connecting them to each other as well as to oxytalan fibers [5]. Microfibrils that include the fibulins, fibrillins, and microfibrilassociated glycoproteins, restore the vessel wall to its resting conditions after systolic expansion [5, 7]. Collagen fibers and the microarchitecture that connect them prevent “mechanical failure” of the vessel under the constant loading of arterial pressure and its further increase during systole [7]
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