Mechanotransduction In Vascular Cells Research Articles

Emerging role of YAP/TAZ in vascular mechanotransduction and disease.

Cells have an incredible ability to physically interact with neighboring cells and their environment. They can detect and respond to mechanical forces by converting mechanical stimuli into biochemical signals in a process known as mechanotransduction. This is a key process for the adaption of vascular smooth muscle and endothelial cells to altered flow and pressure conditions. Mechanical stimuli, referring to a physical force exerted on cells, are primarily sensed by transmembrane proteins and the actin cytoskeleton, which initiate a cascade of intracellular events, including the activation of signaling pathways, ion channels, and transcriptional regulators. Recent work has highlighted an important role of the transcriptional coactivators YAP/TAZ for mechanotransduction in vascular cells. Interestingly, the activity of YAP/TAZ decreases with age, providing a potential mechanism for the detrimental effects of aging in the vascular wall. In this review, we summarize the current knowledge on the functional role of YAP and TAZ in vascular endothelial and smooth muscle cells for mechanotransduction in homeostasis and disease. In particular, the review is focused on invivo observations from conditional knockout (KO) models of YAP/TAZ and the potential implications these studies may have for our understanding of vascular disease development.

Nuclear Mechanosensation and Mechanotransduction in Vascular Cells.

Vascular cells are constantly subjected to physical forces associated with the rhythmic activities of the heart, which combined with the individual geometry of vessels further imposes oscillatory, turbulent, or laminar shear stresses on vascular cells. These hemodynamic forces play an important role in regulating the transcriptional program and phenotype of endothelial and smooth muscle cells in different regions of the vascular tree. Within the aorta, the lesser curvature of the arch is characterized by disturbed, oscillatory flow. There, endothelial cells become activated, adopting pro-inflammatory and athero-prone phenotypes. This contrasts the descending aorta where flow is laminar and endothelial cells maintain a quiescent and atheroprotective phenotype. While still unclear, the specific mechanisms involved in mechanosensing flow patterns and their molecular mechanotransduction directly impact the nucleus with consequences to transcriptional and epigenetic states. The linker of nucleoskeleton and cytoskeleton (LINC) protein complex transmits both internal and external forces, including shear stress, through the cytoskeleton to the nucleus. These forces can ultimately lead to changes in nuclear integrity, chromatin organization, and gene expression that significantly impact emergence of pathology such as the high incidence of atherosclerosis in progeria. Therefore, there is strong motivation to understand how endothelial nuclei can sense and respond to physical signals and how abnormal responses to mechanical cues can lead to disease. Here, we review the evidence for a critical role of the nucleus as a mechanosensor and the importance of maintaining nuclear integrity in response to continuous biophysical forces, specifically shear stress, for proper vascular function and stability.

An Analytical Investigation of in Vivo Mechanical References for Mechanobiological Experiments of Vascular Cells

Blood vessels interact with their mechanical environments in a comprehensive way. Local mechanical stimuli outside the biological range play important roles in various human cardiovascular diseases. Although many mechanobiological studies of endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) in vitro have been reported in mimicking cellular dysfunctions, their quantitative correlations to the in vivo vascular conditions remain unclear. In order to interpret the stress-modulated dysfunctions of vascular cells and explore the key mechanical factors in vascular diseases, it is important to investigate the mechanical environments of vessel walls in vivo under various physiological conditions. Based on nonlinear continuum mechanics, we analyzed the variations of the mechanical stress, strain, and wall stiffness in human blood vessels at different blood pressures. We adopted nine middle-aged arteries located at different physiological sites for stress analysis including three aortas (ascending thoracic, descending thoracic, and abdominal), and five arterial branches (common iliac, femoropopliteal, subclavian, common carotid, and renal, and left anterior descending coronary artery). The femoropopliteal arteries aged from 11 to 70 years were also adopted for investigating the aging effects. It is found that 1) the vascular cells experience various mechanical stimuli along the arterial tree; 2) the intima and adventitia exhibit distinct variations in stress and strain during the femoropopliteal artery aging; and 3) the magnitude of wall stiffness seems to depend on the arterial locations rather than aging. Although it is reported that stress concentration usually occurs in intima causing EC dysfunctions, our results suggest that the adventitia is more likely to bear high stresses in middle-aged aortas and aged femoropopliteal arteries, triggering the vascular inflammation. We conclude that the mechanical niches of vascular cells strongly depend on the physiological site and aging process. The present results contribute to a better understanding of the mechanical environments in vessel walls, which could serve as a reference for studying the vascular cell mechano-transduction.

The Role of Syndecan‐1 in Arterial Mechanotransduction

Hemodynamic forces induced by blood flow are potent regulators of vascular homeostasis and arterial structure. While previous work has focused on the role of integrin receptors in mechanotransduction, little is known about the role of cell surface proteoglycans in these processes. This work focuses specifically on the role of the cell surface heparan sulfate proteoglycan syndecan‐1 in vascular cell mechanotransduction. We isolated vascular smooth muscle cells from syndecan‐1 knockout mice and tranfected them with wild‐type and mutated forms of syndecan‐1 using lentiviral vectors. Wild‐type, syndecan‐1 knockout and mutated syndecan‐1 overexpressing mouse vascular smooth muscle cells were cultured in plates with collagen coated silicone membranes. The cells were then subjected to 10% strain at 1 Hz biaxial or uniaxial loads for up to two hours. We found that syndecan‐1 knockout or deletion of the cytoplasmic region of syndecan‐1 caused an increase in actin stress fibers and focal adhesion sites in response to mechanical strain. Further, knockout of syndecan‐1 led to enhanced ERK and Src phosphorylation in response to mechanical strain. These findings support that syndecan‐1 is an important mediator of mechanotransduction in vascular cells.

Molecular mechanisms of the vascular responses to haemodynamic forces

Blood vessels are permanently subjected to mechanical forces in the form of stretch, encompassing cyclic mechanical strain due to the pulsatile nature of blood flow and shear stress. Significant variations in mechanical forces, of physiological or physiopathological nature, occur in vivo. These are accompanied by phenotypical modulation of smooth muscle cells and endothelial cells, producing structural modifications of the arterial wall. In all the cases, vascular remodelling can be allotted to a modification of the tensional strain or shear, and underlie a trend to reestablish baseline mechanical conditions. Vascular cells are equipped with numerous receptors that allow them to detect and respond to the mechanical forces generated by pressure and shear stress. The cytoskeleton and other structural components have an established role in mechanotransduction, being able to transmit and modulate tension within the cell via focal adhesion sites, integrins, cellular junctions and the extracellular matrix. Mechanical forces also initiate complex signal transduction cascades, including nuclear factor-kappaB and mitogen-activated protein kinase pathways, leading to functional changes within the cell.