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Hyaluronan: A critical regulator of endothelial-to-mesenchymal transition during cardiac valve formation.

Anne Karine Lagendijk, András Szabó, Roeland M.H. Merks and Jeroen Bakkers. Hyaluronan: A critical regulator of endothelial-to-mesenchymal transition during cardiac valve formation. Trends in Cardiovascular Medicine, 23(2013), 135–142

During embryonic development cardiac valves arise at specific regions in  the cardiac endothelium that swell up due to enhanced extracellular  matrix production (so called endocardial cushions). An important  extracellular matrix component that is produced by the endocardial cells  is the glycosaminoglycan hyaluronan. A deficiency in hyaluronan  synthesis results in a failure to form endocardial cushions and a loss  of their cellularization by a process called endothelial-to-mesenchymal  transformation. Expression of the major hyaluronan synthase Has2 is  under the influence of both positive and negative regulators. MicroRNA  dependent degradation of Has2 is required to control extracellular  hyaluronan levels and thereby the size of the endocardial cushions. In  this article we review the current literature on hyaluronan synthesis  during cardiac valve formation and propose that a balanced activity of  both positive and negative regulators is required to maintain the  critical homeostasis of hyaluronan levels in the extracellular matrix  and thereby the size of the endocardial cushions.  The activating and  inhibitory interactions between microRNA-23, Has2 and hyaluronan are  reminiscent of a reaction-diffusion system. Using a mathematical  modeling approach we show that the system can produce a confined  expression of hyaluronan, but only if the inhibitory signal is  transferred to adjacent cells in exosomes. Trends in Cardiovascular Medicine (2013), 23:135–142.