Radiosensitive Smooth Muscle Cells Populate Neointimal Lesions Through a Platelet Derived Growth Factor Receptor Beta Dependent Mechanism
Griffith, Steven, Biochemistry and Molecular Genetics - Graduate School of Arts and Sciences, University of Virginia
Owens, Gary, Department of Molecular Phys and Biological Physics, University of Virginia
Objective: To provide direct evidence supporting or refuting the dogma that SMC-specific 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. 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 SMC-derived 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.
PHD (Doctor of Philosophy)
SMC, Smooth Muscle Cell, Radiosensitive, Bone Marrow Transfer, Vascular Injury, Carotid Ligation, Lineage Tracing, Injury Resolution, Platelet Derived Growth Factor Receptor Beta, PDGFRB