serotonin potentiates transforming growth factor-beta3 induced biomechanical remodeling in avian embryonic atrioventricular valves血清素强化转型增长factor-beta3诱导禽类胚胎房室瓣膜生物力学改造.pdfVIP

Serotonin Potentiates Transforming Growth Factor-beta3 Induced Biomechanical Remodeling in Avian Embryonic Atrioventricular Valves 1 2 3 2 Philip R. Buskohl , Michelle L. Sun , Robert P. Thompson , Jonathan T. Butcher * 1 Department of Mechanical and Aerospace Engineering, Cornell University, Ithaca, New York, United States of America, 2 Department of Biomedical Engineering, Cornell University, Ithaca, New York, United States of America, 3 Department of Cell Biology and Regenerative Medicine, Medical University of South Carolina, Charleston, South Carolina, United States of America Abstract Embryonic heart valve primordia (cushions) maintain unidirectional blood flow during development despite an increasingly demanding mechanical environment. Recent studies demonstrate that atrioventricular (AV) cushions stiffen over gestation, but the molecular mechanisms of this process are unknown. Transforming growth factor-beta (TGFb) and serotonin (5-HT) signaling modulate tissue biomechanics of postnatal valves, but less is known of their role in the biomechanical remodeling of embryonic valves. In this study, we demonstrate that exogenous TGFb3 increases AV cushion biomechanical stiffness and residual stress, but paradoxically reduces matrix compaction. We then show that TGFb3 induces contractile gene expression (RhoA, aSMA) and extracellular matrix expression (col1a2) in cushion mesenchyme, while simultaneously stimulating a two- fold increase in proliferation. Local compaction increased due to an elevated contractile phenotype, but global compaction appeared reduced due to proliferation and ECM synthesis. Blockade of TGFb type I receptors via SB431542 inhibited the TGF b3 effects. We next showed that exogenous 5-HT does not influence cushion stiffness by itself,