Mesothelial and Mural Cell Contribution to Vascular Development through PDGF Signaling
French, Wendy Joy
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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.