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dc.contributor.authorBalachandran, Kartik
dc.contributor.authorAlford, Patrick W.
dc.contributor.authorWylie-Sears, Jill
dc.contributor.authorGoss, Josue
dc.contributor.authorGrosberg, Anna
dc.contributor.authorBischoff, Joyce E.
dc.contributor.authorAikawa, Elena
dc.contributor.authorLevine, Robert A.
dc.contributor.authorParker, Kevin Kit
dc.date.accessioned2015-08-10T16:54:04Z
dc.date.issued2011
dc.identifier.citationBalachandran, K., P. W. Alford, J. Wylie-Sears, J. A. Goss, A. Grosberg, J. Bischoff, E. Aikawa, R. A. Levine, and K. K. Parker. 2011. “Cyclic Strain Induces Dual-Mode Endothelial-Mesenchymal Transformation of the Cardiac Valve.” Proceedings of the National Academy of Sciences 108 (50) (November 28): 19943–19948. doi:10.1073/pnas.1106954108.en_US
dc.identifier.issn0027-8424en_US
dc.identifier.issn1091-6490en_US
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:17985221
dc.description.abstractEndothelial-mesenchymal transformation (EMT) is a critical event for the embryonic morphogenesis of cardiac valves. Inducers of EMT during valvulogenesis include VEGF, TGF-β1, and wnt/β-catenin (where wnt refers to the wingless-type mammary tumor virus integration site family of proteins), that are regulated in a spatiotemporal manner. EMT has also been observed in diseased, strain-overloaded valve leaflets, suggesting a regulatory role for mechanical strain. Although the preponderance of studies have focused on the role of soluble mitogens, we asked if the valve tissue microenvironment contributed to EMT. To recapitulate these microenvironments in a controlled, in vitro environment, we engineered 2D valve endothelium from sheep valve endothelial cells, using microcontact printing to mimic the regions of isotropy and anisotropy of the leaflet, and applied cyclic mechanical strain in an attempt to induce EMT. We measured EMT in response to both low (10%) and high strain (20%), where low-strain EMT occurred via increased TGF-β1 signaling and high strain via increased wnt/β-catenin signaling, suggesting dual strain-dependent routes to distinguish EMT in healthy versus diseased valve tissue. The effect was also directionally dependent, where cyclic strain applied orthogonal to axis of the engineered valve endothelium alignment resulted in severe disruption of cell microarchitecture and greater EMT. Once transformed, these tissues exhibited increased contractility in the presence of endothelin-1 and larger basal mechanical tone in a unique assay developed to measure the contractile tone of the engineered valve tissues. This finding is important, because it implies that the functional properties of the valve are sensitive to EMT. Our results suggest that cyclic mechanical strain regulates EMT in a strain magnitude and directionally dependent manner.en_US
dc.description.sponsorshipEngineering and Applied Sciencesen_US
dc.language.isoen_USen_US
dc.publisherProceedings of the National Academy of Sciencesen_US
dc.relation.isversionofdoi:10.1073/pnas.1106954108en_US
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pubmed/22123981en_US
dash.licenseLAA
dc.subjecttight junctionsen_US
dc.subjectcytokinesen_US
dc.subjectactivated myofibroblasten_US
dc.titleCyclic Strain Induces Dual-Mode Endothelial-Mesenchymal Transformation of the Cardiac Valveen_US
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden_US
dc.relation.journalProceedings of the National Academy of Sciencesen_US
dash.depositing.authorParker, Kevin Kit
dash.waiver2011-10-06
dc.date.available2015-08-10T16:54:04Z
dc.identifier.doi10.1073/pnas.1106954108*
dash.contributor.affiliatedGoss, Josue
dash.contributor.affiliatedParker, Kevin
dash.contributor.affiliatedBischoff, Joyce
dash.contributor.affiliatedAikawa, Elena
dash.contributor.affiliatedLevine, Robert


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