Molecular Mechanisms of Atherosclerosis
Integrating Mechanical Cues into Biological Signals
Oct 19, 2009
Consider the flow of blood through the human cardiovascular system. Endothelial cells, which line blood vessels, are influenced by hemodynamic stresses that arise due to blood flow. This is an example of a process termed mechanotransduction, the transmission and translation of mechanical force into biochemical signals. Proliferation, cell alignment and cytoskeletal arrangement, gene expression, and nitric oxide production are all shown to be regulated by shear stress. Changes in stress profiles therefore play an important role in the localization and development of atherosclerotic lesions, the dangerous plaques that form due to perturbed endothelial cell biology.
Potential Molecular Mechanisms
An extensive research database characterizes the signaling cascades that result from mechanical stress. However, a strong understanding of the initiating process(es) is still lacking. The current view in the field is that mechanisms by which endothelial cells sense and transduce hydrodynamic forces are likely varied, and there is probably interplay between them.
Potential contributing mechanisms under active investigation include changes in membrane fluidity, effects of the glycocalyx, the role of ion channels, and changes in protein interactions within focal adhesions.
Cell Membrane Fluidity
Fluid shear stress has been shown to increase the membrane fluidity of endothelial cells, where work published by Prof Shu Chien's lab in 2001 in the American Journal of Physiology – Cell Physiology titled "Shear Stress Induces a Time- and Position-Dependent Increase in Endothelial Cell Membrane Fluidity", indicates a differential increase between upstream and downstream elements. Upstream diffusivity reaches a peak at 7 minutes before decreasing despite continued shear stress application. This result relates to G protein activity, which was stimulated by artificially increasing membrane fluidity. G proteins regulate downstream signaling pathways by acting as 'molecular switches' that cycle between active (GTP bound) and inactive (GDP bound) states. Thus the cell membrane itself might be a transducer of force.
Glycocalyx
The glycocalyx consists of glycosaminoglycan chains, well-arranged and standing tall like wheatgrass on the cell surface facing the lumen. Prof Sheldon Weinbaum and co-authors review the glycocalyx in an article published in a 2007 edition of the Annual Review of Biomedical Engineering, "The Structure and Function of the Endothelial Glycocalyx Layer". The glycocalyx provides a barrier to shear stress, resulting in an essentially zero force being exerted on the top plasma membrane. The presence of an intact glycocalyx layer is necessary for the shear stress-induced suppression of motility and proliferation, and the glycocalyx itself is modulated by shear stress. It has thus been proposed that the force transmitted through the glycocalyx to its membrane anchors is responsible for mediating mechanotransduction.
Ion Channels
Ion channels are also implicated in mechanotransduction. The inward-rectifying potassium current is activated upon shear stress along with an increase in calcium influx in endothelial cells. According to a paper published in 2001 in Physiological Review by Dr Bernd Nilius and co-author, titled "Ion Channels and their Functional Role in Vascular Endothelium", this influx could in turn regulate the activation of other potassium- and calcium-activated channels, providing the initial trigger for a signaling cascade. Calcium influx could also lead to production of bioactive agents such as nitric oxide.
Focal Adhesion Proteins
The least investigated mechanism is that of changes in protein binding energy within the focal adhesion due to external mechanical forces. Focal adhesions are sites of cellular attachment to the basal membrane and allow direct communication between the extracellular matrix and the cell’s intracellular elements. A collection of more than fifty different proteins has been shown to reside in focal adhesions. Focal adhesion proteins talin and vinculin, for example, are known to have cryptic binding sites that are exposed upon force application. The suggestion put forward by Prof Kamm and co-author in a 2004 paper, "On the Molecular Basis for Mechanotransduction", published in Mechanics & Chemistry of Biosystems, is that mechanical force could influence any number of focal adhesion proteins and induce protein conformational change, which would ultimately result in changes in binding affinity and / or enzyme activity. Downstream signaling cascades would subsequently be affected.
Driven by scientific curiosity, researchers continue to work on further illuminating the details of this complex mechanobiological interplay, with the hope of being able to pull apart the different pieces that lead to atherosclerosis.
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