Roles of Fibronectin and Integrin α5 in Pharyngeal Arch Artery Morphogenesis
Congenital cardiovascular defects are among the most prevalent human birth defects. Studies of the pathogenesis of these diseases have revealed developmental alterations in embryonic pharyngeal region, in which numerous genes in distinct tissues are under spatiotemporal regulation during embryonic cardiovascular morphogenesis. The signaling interactions and crosstalks between embryonic pharyngeal tissues are potentially orchestrated by extracellular matrix. Fibronectin and its integrin receptors are important mediators for cell-matrix interaction, and they have been strongly implicated in early cardiovascular morphogenesis. However, the understanding on the role of fironectin-integrin signaling in cardiovascular development was hindered by early embryonic lethality and the complexity of various developmental defects in multiple systems in global knockout models. To circumvent these issues for our novel investigation, we used Isl1cre knock-in mouse strain to conditionally ablate fibronectin or integrin α5 in distinct tissues of the embryonic pharynx, an environment of fibronectin enrichment and of pivotal importance for cardiovascular morphogenesis. The mutants displayed malformations of aortic arch arteries correlated with defective formation of the 4th Pharyngeal Arch Arteries (PAAs), a characteristic phenotype resembling those in human DiGeorge syndrome. To understand the underlying mechanism, we investigated the normal and defective vascular morphogenesis of PAA by quantitatively analyzing the endothelial population in the 4th pharyngeal arch using three-dimensionally reconstructed confocal imaging technique. Our data suggest that PAA formation is a process of vasculogenesis from mesoderm followed by remodeling of microvascular network. The initial formation and the subsequent growth of PAA rely on on vascular coalescence with dynamic endothelial re-distribution. Deficiency of fibronectin or integrin α5 in distinct tissues of the pharyngeal microenvironment compromises vasculogenesis and the subsequent vascular remodeling, which leads to defective PAA morphogenesis. Our collective findings provide novel insight into extracellular matrix-mediated embryonic vascular patterning.
Chen, Dongying, "Roles of Fibronectin and Integrin α5 in Pharyngeal Arch Artery Morphogenesis" (2016). ETD Collection for Thomas Jefferson University. AAI10017953.