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Cardiac valves development directly depends on two proteins sensitive to blood flows forces


The embryonic formation of the cardiac valves allows the blood flow to favor little by little a one-way circulation.

The expression level of the gene klf2a and the formation of the cardiac valves depend on flow oscillations intensity that induce an increase in intracellular Ca+ rates via Trpv4 and Trpp2 ionic channels.



May 12, 2015

The team of Julien Vermot at IGBMC has evidenced how the mechanical forces generated by blood flows activate the embryonic cardiac valves formation. They show that force sensing is mediated by two transient receptor channel, Trpv4 and Trpp2 (or PC2).

Cardiac valves anomalies are among the most frequent human cardiovascular system anomalies and abnormal valve are usually replaced by valve transplantation directly in the patient.

These results lead to a better understanding of the contribution of mechanical forces during cardiac morphogenesis and might contribute to optimize in vitro valves formation.
These results are published on May 7th, 2015 in the Current Biology.



In vertebrate animals, the cardiac activity plays a key role during heart formation. The cardiac valves are essential as they are "anti-return lids" which allow the pumping of blood in a single direction.

Myocardial contractility and its associated forces are is essential to valve development as it is necessary to activate the expression of essential genes associated to cardiogenesis.

Recently, Julien Vermot's team showed that the oscillatory blood flow is enhanced in the area where heart valve will form and for the activation of the expression of the gene klf2a, known for its major anti-atherosclerotic functions. The researchers showed that the oscillating flows generated in the heart are sensed by the endocardial cells that will form the valves. The mechanism by which these cells sense flow remained unknown.

In their last study, the group proposes the molecular mechanism: they identified two channels sensitive to mechanical strengths that are activated in response of the oscillatory flows intensity and control directly the genesis of valves by modifying the endocardial cells response.

Through the direct observation of cardiac blood cells movements and the use of mathematical modeling, they quantified the mechanical forces applied to the endocardium walls during the formation of valves. They demonstrated that these forces directly influence the response of endothelial cells.

They characterized the cell response by quantifying endocardial calcium increase and klf2a gene promoter response through high resolution live imaging. They used cutting edge microscopy technics as well as tailored image processing tools to quantify the cell response. This led them to propose that endocardial cell response to flow are modulated by blood flow oscillation amplitude through two proteins: Trpv4 and Trpp2 (or PC2).

Importantly, they show that valves do not grow normally when these two proteins are absent. Furthermore, they can rescue the activation of calcium and klf2a rates when the oscillations intensity is decreased by using chemical drugs that are activating trpv4. This suggests that mechanical forces can be bypassed by directly stimulating these channels with the proper drug.

This mechanical mechanism involved in the formation of the cardiac valves of vertebrates in vivo might permit to improve the manufacturing process of valves generated in vitro.



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