Methodologic Approaches to Investigate Vascular Tube Morphogenesis and Maturation Events in 3D Extracellular Matrices In Vitro and In Vivo
De novo blood vessel formation is regulated by two major processes, termed vasculogenesis and angiogenesis. A key aspect of this formation is the process of endothelial cell (EC) lumen and tube assembly. Major advances have been made in our understanding of the EC lumen formation process primarily through the development and utilization of in vitro models of this process in 3D extracellular matrices. Recent advances include the identification of an EC lumen signaling complex that controls EC tubulogenesis in 3D collagen matrices and determination of growth factor requirements that are required for these events under serum-free defined conditions. Components of the lumen signaling complex include the collagen-binding integrin, α2β1, the membrane-type 1 matrix metalloproteinase, MT1-MMP, junction adhesion molecules B and C, Par3, Par6b and the Rho GTPase, Cdc42. This complex of proteins controls EC lumen and tube formation and establishes the signaling conditions necessary to both form and sustain an EC tube network in 3D matrices. This EC tube network induces the recruitment of pericytes which then affect tube and extracellular matrix remodeling events to regulation the maturation of tubes. Methodologies utilized to address these events are presented to illustrate how the cellular and molecular basis for EC tube morphogenesis and stabilization are currently investigated.
KeywordsTube Formation Stem Cell Factor Vascular Basement Membrane Vascular Morphogenesis Endothelial Cell Tube
This work was supported by NIH grants HL59373, HL79460, HL87308, and HL105606 to GED.
- 26.Davis GE, Stratman AN, Sacharidou A (2011) Molecular control of vascular tube morphogenesis and stabilization: regulation by extracellular matrix, matrix metalloproteinases and endothelial cell-pericyte interactions. In: Gerecht S (ed) Biophysical regulation of vascular differentiation. Springer, New York, pp 17–47CrossRefGoogle Scholar
- 27.Bell SE, Mavila A, Salazar R et al (2001) Differential gene expression during capillary morphogenesis in 3D collagen matrices: regulated expression of genes involved in basement membrane matrix assembly, cell cycle progression, cellular differentiation and G-protein signaling. J Cell Sci 114:2755–2773PubMedGoogle Scholar
- 29.Davis GE, Pintar Allen KA, Salazar R et al (2001) Matrix metalloproteinase-1 and −9 activation by plasmin regulates a novel endothelial cell-mediated mechanism of collagen gel contraction and capillary tube regression in three-dimensional collagen matrices. J Cell Sci 114:917–930PubMedGoogle Scholar