UNASSIGNED: During valvulogenesis, globular endocardial cushions elongate and remodel into highly organized thin fibrous leaflets. Proper regulation of this dynamic process is essential to maintain unidirectional blood flow as the embryonic heart matures. In this study, we tested how mechanosensitive small GTPases, @entity3547 and @entity5180 , coordinate atrioventricular valve (AV) differentiation and morphogenesis. @entity3547 activity and its regulated GTPase-activating protein @entity69228 are elevated during early cushion formation but decreased considerably during valve remodeling. In contrast, @entity5180 activity was nearly absent in the early cushions but increased substantially as the valve matured. Using gain- and loss-of-function assays, we determined that the @entity3547 pathway was essential for the contractile myofibroblastic phenotype present in early cushion formation but was surprisingly insufficient to drive matrix compaction during valve maturation. The @entity5180 pathway was necessary to induce matrix compaction in  vitro through increased cell adhesion, elongation, and stress fiber alignment. Facilitating this process, we found that acute cyclic stretch was a potent activator of @entity3547 and subsequently downregulated @entity5180 activity via @entity69228 . On the other hand, chronic cyclic stretch reduced active @entity3547 and downstream @entity69228 , which enabled @entity5180 activation. Finally, we used partial atrial ligation experiments to confirm in  vivo that altered cyclic mechanical loading augmented or restricted cushion elongation and thinning, directly through potentiation of active @entity5180 and active @entity3547 , respectively. Together, these results demonstrate that cyclic mechanical signaling coordinates the @entity3547 to @entity5180 signaling transition essential for proper @entity339 .

Cyclic Mechanical Loading Is Essential for XXXX -Mediated Elongation and Remodeling of the Embryonic Mitral Valve.

@entity339 :: ('MESH:D008944', 'Disease') :: ['embryonic mitral valve remodeling'] @entity3547 :: ('387', 'Gene') :: ['RhoA'] @entity5180 :: ('5879', 'Gene') :: ['Rac1'] @entity69228 :: ('83478', 'Gene') :: ['FilGAP']
@entity5180 :: (5879,Gene) :: ['Rac1']
