PDGFR B Signaling in Mouse Epicardial and Mural Cells Influences Blood Vessel Remodeling
Mellgren, Amy Marie
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Platelet derived growth factor receptor beta (PDGFRbeta) is a receptor tyrosine kinase expressed in vascular smooth muscle cells (VSMC), which promotes proliferation and migration. We provide evidence of additional roles for the PDGFRbeta prior to the differentiation of VSMC. We show that PDGFRbeta, as well as PDGFRalpha, is expressed in epicardial and subepicardial mesenchymal cells, which are precursors for coronary VSMC. We demonstrate that PDGFRbeta-/- mice exhibit a lack of coronary VSMC and have disrupted endothelial vessels on the ventral surface of the heart; however, neither conditional ablation of the PDGFRbeta with an SM22 Cre Tg, which is expressed in differentiated VSMC, nor with a myocardinCre, which has an earlier expression profile and is believed to control VSMC differentiation, phenocopy the lack of coronary VSMC found in PDGFRbeta-/- mice. Further investigations into PDGFRbeta-/- mice revealed a defect in the function of the epicardium. The epicardium exhibited an altered cellular morphology and a decreased ability to migrate into the myocardium both in vivo and ex vivo. The decreased motility was associated with a nonpolarized distribution of actin and a lack of localization of Arp2/3 to the cell periphery. Moreover, these defects appeared to be dependent on the Src signaling pathway. This work thus establishes a novel in vivo role for the PDGFRbeta at a stage of coronary VSMC development during which the epicardium undergoes cytoskeletal rearrangement in order to efficiently migrate into the myocardium and form the mesenchymal precursors of coronary VSMC. In addition to this role in vasculogenesis, we demonstrate a role for the PDGFRbeta in angiogenesis. Using point mutations in PDGFRbeta we generated mice that possessed variations in the number of pericytes that were present in tissues, including the trachea and retina. We then utilized these mutant mouse lines to show that a decrease in pericytes affects the ability of the vasculature to respond to an angiogenic agent, Ang1. Moreover, this response is not secondary to hypoxia. This work emphasizes the value of targeting both VSMC and endothelial cells in therapies targeting vessel regeneration.