Browsing by Subject "Receptor, Platelet-Derived Growth Factor beta"
Now showing 1 - 2 of 2
- Results Per Page
- Sort Options
Item Mesothelial and Mural Cell Contribution to Vascular Development through PDGF Signaling(2009-06-17) French, Wendy Joy; Tallquist, Michelle D.Vascular development during embryogenesis and adulthood occurs through vasculogenesis and angiogenesis. Vasculogenesis is the de novo formation of blood vessels from mesoderm precursor cells. Angiogenesis is the formation of new vessels from existing vessels. Both processes involve hematopoietic, endothelial, and mural cells for the formation of mature, stable vasculature. While hematopoietic and endothelial cell contributions and function in vascular development have been extensively studied identifying the VEGF and TGF families as major contributors, the role of mural cells has not been clearly defined. The platelet derived growth factor beta (PDGFR beta) is essential for mural cell recruitment and expansion. Deletion of PDGFR beta leads to perinatal lethality resulting from vascular defects attributed to severe decreases in mural cells. PDGFR beta is a receptor tyrosine kinase with high homology in signal activation to PDGFR alpha. Downstream signaling pathway activation includes PI3 kinase, Src, RasGAP, Grb2, Shp-2, and PLC?gamma for the regulation of cellular functions.The focus of this research was to determine the temporal and functional requirements of PDGFR signaling in mural cells. To address the temporal requirements for PDGFR beta, genetic manipulation was used to delete the receptor in precursor and differentiated mural cells. In addition, mutant mice were generated with the additional deletion of PDGFR alpha to address the potential for compensatory or cooperative function between the two receptors. These studies identified a cooperative role for PDGFR?alpha and PDGFR beta in yolk sac mesothelial cells. Mutant mice were lethal around E10.5 with disrupted yolk sac vascular remodeling and extracellular matrix composition. The PDGFR regulate collagen matrix through regulation of matrix metalloproteinase activity and thus disrupt integrin activation. The functional role of PDGFR?beta in mural cells was addressed by signaling point mutants targeting and disrupting specific downstream pathways. These studies resulted in a progressive decrease in mural cells that correlated to the number of disrupted PDGFR-beta signaling pathways. Together these analyses demonstrate PDGFR and mural cells are essential for vascular development and maintenance.Item PDGFR B Signaling in Mouse Epicardial and Mural Cells Influences Blood Vessel Remodeling(2009-06-15) Mellgren, Amy Marie; Tallquist, Michelle D.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.