Role of Mechanotransduction in Vascular Biology

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 chemo-mechanical 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.

Vascular disease-causing mutation, smooth muscle α-actin R258C, dominantly suppresses functions of α-actin in human patient fibroblasts

“…Our findings are significant in establishing cytoskeletal effects of the mutation in a cellular context with the ACTA2 +/R258C genotype. Thoracic aortic aneurysms and dissections are understood to result from dysfunctional mechanosensing and mechanoregulation of the extracellular matrix by intramural cells, leading to compromised structural integrity of the aortic wall (14). Our results point to the possibility that, in addition to affecting vascular smooth muscle cells, ACTA2 mutations may also compromise adventitial myofibroblasts in responding to mechanical stresses and remodeling the adventitial sheath to protect against rupture.…”

“…Additionally, actin plays an important role in modulating transcription of vascular muscle contractile protein genes via its interaction with MRTF-A. Extrapolating from the deleterious impact of R258C SM α-actin on myosin-dependent force production with isolated thin filaments (17) and on mutant fibroblast matrix contractions (herein), we hypothesize that aortic smooth muscle force production will be compromised in patients with the R258C ACTA2 missense mutation, leading to dysfunctional mechanical homeostasis and structural failure (14). Interestingly, affected individuals show little disruption in function of nonvascular smooth muscle tissues (16).…”

“…Dissected aortas exhibit characteristic features, including loss and disarray of smooth muscle cells in the medial layer, loss of elastic fibers, and proteoglycan accumulation in the medial space (4). These observations have led to the hypothesis that TAADs arise because of inappropriate mechanosensing and mechanoregulation of the extracellular matrix by aortic smooth muscle cells (5,14,15). Such deficits are believed to make the aortic wall vulnerable to dilation and dissection.…”

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

“…Under physiological circumstances, elastin is thought to only be secreted and productively deposited by VSMCs during the fetal and neonatal periods (Davis 1993;Kelleher et al 2004). Both mechanical stimuli and biochemical signals regulate the interaction between the ECM and vascular cells Mack 2011;Humphrey et al 2015). Changes in the ECM are sensed by vascular cells through matrix-binding receptors, such as integrins, and influence cell migration, proliferation, and survival (Moiseeva 2001); in turn, vascular cells can modify the composition and structure of the ECM by increasing or decreasing secretion of matrix proteins and matrix-remodeling enzymes (Leung et al 1976;O'Callaghan and Williams 2000).…”

Vascular disease-causing mutation R258C in ACTA2 disrupts actin dynamics and interaction with myosin

“…Our results predict that cells expressing the R258C mutation will have decreased force output and a larger pool of monomeric actin. These dysfunctions could trigger aberrant mechanosensing pathways that culminate in compromised aortic muscle tissue (13). Increasing the monomer/polymer ratio of actin may also have an impact on cellular phenotype, which could have implications for occlusive vascular disease.…”