Persistent Link:
http://hdl.handle.net/10150/194478
Title:
Mechanisms of Cardiovascular Development
Author:
Rodgers, Laurel Speilman
Issue Date:
2009
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Abstract:
Epithelial to mesenchymal transition (EMT) is an essential process during embryogenesis for the development of organ systems, including the heart and its vasculature. The development of both coronary vessels and heart valves depends on EMT. In this dissertation, we first present data demonstrating that increasedoligosaccharide hyaluronan (o-HA) levels after EMT induction within atrioventricular (AV) valves leads to a decrease in EMT due to the induction of VEGF expression. Regulated EMT inhibition prevents the formation of hyperplastic valves. Next, we show that the proepicardium, which provides the precursor cells required for epicardial and coronary vessel development, migrates to the developing heart via direct contact of multicellular proepicardial villi to the developing myocardium. This shifts the paradigm from a migration consisting of floating cysts to one of direct contact and differential adhesion forces to form the initial epicardium. A subset of epicardial cells undergoes EMT, migrates into the developing heart, and differentiates into cardiac fibroblast, vascular endothelial, and smooth muscle cells. In order to more effectively study epicardial EMT in vitro, we developed several new methods for the in vitro study of coronary vessel development. We developed an improved protocol for isolating embryonic myocyte cells, for use in co-cultures with epicardial cells. This co-culture system allows investigation into the effects of myocyte derived soluble factors uponepicardial EMT and mesenchymal cell differentiation. We also present a protocol for isolating epicardial clonal colonies from an epicardial cell line derived from the ImmortoMouse. These clones provided direct evidence that the epicardium is a heterogeneous population of cells. These unique clones allow for to study into specific epicardial cell lineages and phenotypes. Finally, we provide data defining the expression of Wnts within the developing heart and the role may play during epicardial EMT. We conclude that canonical Wnts are both necessary and sufficient to inhibit epicardial EMT. These results provide the first direct evidence for a role of Wnt proteins during coronary vessel development. Collectively our results provide significant advancements in our understanding of EMT regulation during cardiac development.
Type:
text; Electronic Dissertation
Keywords:
AV Valve; Coronary Vessels; Development; Epicardium; Proepicardium; Wnt
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Cell Biology & Anatomy; Graduate College
Degree Grantor:
University of Arizona
Advisor:
Camenisch, Todd D.; Runyan, Ray B.

Full metadata record

DC FieldValue Language
dc.language.isoenen_US
dc.titleMechanisms of Cardiovascular Developmenten_US
dc.creatorRodgers, Laurel Speilmanen_US
dc.contributor.authorRodgers, Laurel Speilmanen_US
dc.date.issued2009en_US
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.abstractEpithelial to mesenchymal transition (EMT) is an essential process during embryogenesis for the development of organ systems, including the heart and its vasculature. The development of both coronary vessels and heart valves depends on EMT. In this dissertation, we first present data demonstrating that increasedoligosaccharide hyaluronan (o-HA) levels after EMT induction within atrioventricular (AV) valves leads to a decrease in EMT due to the induction of VEGF expression. Regulated EMT inhibition prevents the formation of hyperplastic valves. Next, we show that the proepicardium, which provides the precursor cells required for epicardial and coronary vessel development, migrates to the developing heart via direct contact of multicellular proepicardial villi to the developing myocardium. This shifts the paradigm from a migration consisting of floating cysts to one of direct contact and differential adhesion forces to form the initial epicardium. A subset of epicardial cells undergoes EMT, migrates into the developing heart, and differentiates into cardiac fibroblast, vascular endothelial, and smooth muscle cells. In order to more effectively study epicardial EMT in vitro, we developed several new methods for the in vitro study of coronary vessel development. We developed an improved protocol for isolating embryonic myocyte cells, for use in co-cultures with epicardial cells. This co-culture system allows investigation into the effects of myocyte derived soluble factors uponepicardial EMT and mesenchymal cell differentiation. We also present a protocol for isolating epicardial clonal colonies from an epicardial cell line derived from the ImmortoMouse. These clones provided direct evidence that the epicardium is a heterogeneous population of cells. These unique clones allow for to study into specific epicardial cell lineages and phenotypes. Finally, we provide data defining the expression of Wnts within the developing heart and the role may play during epicardial EMT. We conclude that canonical Wnts are both necessary and sufficient to inhibit epicardial EMT. These results provide the first direct evidence for a role of Wnt proteins during coronary vessel development. Collectively our results provide significant advancements in our understanding of EMT regulation during cardiac development.en_US
dc.typetexten_US
dc.typeElectronic Dissertationen_US
dc.subjectAV Valveen_US
dc.subjectCoronary Vesselsen_US
dc.subjectDevelopmenten_US
dc.subjectEpicardiumen_US
dc.subjectProepicardiumen_US
dc.subjectWnten_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineCell Biology & Anatomyen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorCamenisch, Todd D.en_US
dc.contributor.advisorRunyan, Ray B.en_US
dc.contributor.committeememberKrieg, Paul A.en_US
dc.contributor.committeememberGregorio, Carol C.en_US
dc.contributor.committeememberAntin, Parker B.en_US
dc.identifier.proquest10307en_US
dc.identifier.oclc659750927en_US
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