Role of mechanotransduction in vascular biology: focus on thoracic aortic aneurysms and dissections

Abstract

Thoracic aortic diseases that involve progressive enlargement, acute dissection, or rupture are influenced by the hemodynamic loads and mechanical properties of the wall. We have only limited understanding, however, of the mechanobiological processes that lead to these potentially lethal conditions. Homeostasis requires that intramural cells sense their local chemomechanical environment and establish, maintain, remodel, or repair the extracellular matrix to provide suitable compliance and yet sufficient strength. Proper sensing, in turn, necessitates both receptors that connect the extracellular matrix to intracellular actomyosin filaments and signaling molecules that transmit the related information to the nucleus. Thoracic aortic aneurysms and dissections are associated with poorly controlled hypertension and mutations in genes for extracellular matrix constituents, membrane receptors, contractile proteins, and associated signaling molecules. This grouping of factors suggests that these thoracic diseases result, in part, from dysfunctional mechanosensing and mechanoregulation of the extracellular matrix by the intramural cells, which leads to a compromised structural integrity of the wall. Thus, improved understanding of the mechanobiology of aortic cells could lead to new therapeutic strategies for thoracic aortic aneurysms and dissections.

Keywords: Marfan syndrome; actomyosin; elastic fibers; focal adhesion.

Figure 1

TAADs manifest clinically at the macro (tissue) level but result from mechanisms at the micro (molecular) level. Shown are aortic structure and relevant mechanical stresses (see text) that result from hemodynamic loading. The stressed wall consists of three layers (intima, media, adventitia) populated, respectively, by three cell types (endothelial, smooth muscle, fibroblasts). Medial lamellar units consist of many concentric deliminating elastic laminae (elastin plus microfibrils), with associated smooth muscle cells, collagens, and glycosaminoglycans. A unique contractile-elastic unit consists of co-linear extracellular microfibrils connecting through heterodimeric transmembrane complexes (integrins) with intracellular actomyosin filaments to create load-bearing or sensing functions. Linker proteins within the focal adhesion have structural or signaling roles.

Figure 2

Some of the many smooth muscle cell responses to an applied stress (σ) or stretch (λ). Angiotensin II (Ang-II) is a potent vasoconstrictor that also regulates both the production of intracellular contractile and extracellular matrix (ECM) proteins (partly through transforming growth factor-beta, TGF-β, and connective tissue growth factor, CTGF) and the removal of ECM (partly through monocyte chemoattractant protein-1, MCP-1, and thus monocytes/macrophages, MΦ). Matrix metalloproteinases (MMPs) contribute further to matrix removal whereas platelet derived growth factor, PDGF, epidermal growth factor, EGF, and insulin-like growth factor, IGF, contribute to cell proliferation. Finally, stress/stretch activated ionic channels also play important roles in contraction.

Figure 3

Some of the many membrane receptors and associated signaling pathways that are activated by chemo-mechanical stimuli. In many cases, these diverse pathways alter the actomyosin activity that is fundamental to cellular sensing and regulating of the extracellular matrix, which in turn is fundamental to defining aortic compliance and structural integrity. Other pathways, including NF-κB, are similarly important, particularly because of associated inflammation.

Figure 4

Confluence of some of the gene mutations that predispose to thoracic aortic aneurysms and dissections and affect the: mechano-stimulus (e.g., transferal of stress from the matrix to the cell), the mechano-sensing of this stimulus, or the associated mechano-sensitive signaling pathways. See text for information on the affected genes and related references.