Radiosensitive Smooth Muscle Cells Populate Neointimal Lesions Through a Platelet Derived Growth Factor Receptor Beta Dependent Mechanism [thesis]

Steven Griffith
Objective: To provide direct evidence supporting or refuting the dogma that SMCspecific PDGFRB signaling is required for SMC phenotypic switching and neointima formation following vascular injury in vivo. Approach and Results: Utilizing a novel conditional SMC-specific lineage tracing PDGFRB knock out mouse, we demonstrated that PDGFRB signaling is required for SMC phenotypic switching and that loss of PDGFRB in SMCs virtually abolished the capability of SMCs to be recruited into the neointima.
more » ... Loss of PDGFRB in SMCs, however, did not attenuate neointima formation due to compensation by alternative cell types, including myeloid cells. Lethal irradiation and bone marrow transfer experiments revealed neointimas devoid of SMCderived cells in both the WT and KO animals with the majority of the neointima in both genotypes being myeloid derived. Conclusions: Taken together, results demonstrate that there is a radiosensitive subpopulation of SMCs within the vessel wall which normally proliferates and invests the neointima through a PDGFRB dependent mechanism. Further, in the absence of SMC-rich neointimas other cell types including myeloid cells compensate by investing the neointima and activating a subset of SMC marker genes. IV Dedication I dedicate this dissertation to my wife and kids. Without my wife's love, support, and sacrifice I would have not been able to complete my degree. Thank you, Erica, for all of your support, sacrifice, and encouragement! I wouldn't have been able to do this without you. V Acknowledgements I would like to thank my mentor, Gary Owens, for the guidance and support on a project which kept throwing curveballs at us, despite the dogma and everyone supposedly "knowing" what the results should be. This just goes to show that even "safe projects" can have very surprising and exciting results.
doi:10.18130/v3xg8j fatcat:wnjrb7o2jzfsjc4ei3uzq6wvbe