Mechanochemical transduction

Fifty years ago, ECM was considered to be a passive scaffold for cells today we are aware that ECM-cellular communication occurs through mechanical force transduction that affects gene expression and ECM synthesis and that mechanochemical transduction is a key element in modern human physiology and molecular biology. 

It is intriguing to try to analyze if differences in mechanochemical transduction mechanisms could explain why some tissues mineralize normally and others do not. This would make it possible to attempt to analyze why heart valves and vessel walls mineralize abnormally in diseases leading to valvular failure or cardiac insufficiency. 

G proteins are another family of membrane proteins believed to modulate mechanochemical transduction pathways. Mechanical stimulation changes the conformation of G protein that leads to growth-factorlike changes that initiate secondary messenger cascades leading to cell growth. It has been reported that cyclic strain of smooth muscle cells significantly decreased steady-state levels of G protein and adenylate cyclase activity. Muscular stimulation also appears to be coupled with G protein activation in small arteries. 

Although the mechanical behavior of tissues has been studied extensively, we know that interpretation of this behavior is made more complex by the time-dependence, also termed viscoelasticity. Therefore, we examine how the time-dependence can be corrected for in terms of the structural components. The goal of the mechanics sections is to relate mechanical behavior to the composition, arrangement, and environmental conditions that affect each tissue type. Finally, we examine how external forces balance with internal forces to modulate mechanochemical transduction. 

Silver FH, DeVore D, Siperko LM. Role of mechanophysiology in aging of ECM Effects of changes in mechanochemical transduction, J Appl. Physiol. 2003 95 2134. 

We have presented information on the elastic and viscous stress-strain behaviors for a variety of different ECMs in preparation for relating changes in external loading and mechanochemical transduction processes. In order to determine the exact external loading in each tissue that stimulates mechanochemical transduction processes we must take into account the balance between passive loading incorporated into the collagen network in the tissue and active loading applied externally. Inasmuch as the passive load is different for each tissue and is also a function of age (the tension in tissues decreases with age), the net load experienced at the cellular level is difficult to calculate. 

We know from studies of hypertensive animals that blockage of fluid flow in the arterial system not only increases blood pressure but leads to vessel dilation and increases in wall thickness. There appears to be a direct relationship between external (increased blood pressure) mechanical stimulation and up-regulation of mechanochemical transduction processes by increasing the tensile loads that are placed on collagen fibers. This increase in external mechanical stimulation is then directly transferred to smooth muscle cells within the vessel wall. Increased tensile forces lead to increased activation of MAPK pathways as discussed in Chapter 9. We now have the beginning information that details how external mechanical loading influences tissue growth and development. 

Mechanosensing is used to describe the process by which cells sense mechanical forces. Mechanochemical transduction is the phrase that is used to try to describe the biological processes by which external forces such as gravity influence the biochemical and genetic responses of cells and tissues. Specifically, these responses include stimulation of cell proliferation or apoptosis (death) and synthesis or catabolism of components of the extracellular matrix. These processes cause either increases in chemical energy (conversion of amino acids or other small molecules into macromolecules) or decreases in chemical energy (depolymerization of macromolecules). 

There are a number of biochemical components that are involved in mechanochemical transduction processes. We introduce some of the important molecules in an attempt to demonstrate how complex the mechanisms appear to be however, the functions and interrelationships among these molecules are currently unclear. 

A number of protein kinases have been implicated in mechanochemical transduction and activation of phosphorelay systems (see Figures 9.2 to 9.4 for some of these molecules). They include the following. 

Heterotrimeric G proteins transduce a variety of signals generated by interactions with hormones, growth factors, neurotransmitters, and other molecules with cell surface receptors. G proteins are activated in endothelial cells as a result of strain and increased strain-rate phosphorylation of ERK 1/2, which requires G proteins. G proteins are believed to be involved in mechanochemical transduction through adhesion coupled cell mechanosensing. 

Although mechanosensing and mechanochemical transduction processes are likely to be quite complex from a biochemical point of view, we can begin to understand from an engineering point of view how changes in... 

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