Molecular basis of endothelial cell morphogenesis in three‐dimensional extracellular matrices

Abstract

Although many studies have focused on blood vessel development and new blood vessel formation associated with disease processes, the question of how endothelial cells (ECs) assemble into tubes in three dimensions (i.e., EC morphogenesis) remains unanswered. EC morphogenesis is particularly dependent on a signaling axis involving the extracellular matrix (ECM), integrins, and the cytoskeleton, which regulates EC shape changes and signals the pathways necessary for tube formation. Recent studies reveal that genes regulating this matrix-integrin-cytoskeletal (MIC) signaling axis are differentially expressed during EC morphogenesis. The Rho GTPases represent an important class of molecules involved in these events. Cdc42 and Rac1 are required for the process of EC intracellular vacuole formation and coalescence that regulates EC lumen formation in three-dimensional (3D) extracellular matrices, while RhoA appears to stabilize capillary tube networks. Once EC tube networks are established, supporting cells, such as pericytes, are recruited to further stabilize these networks, perhaps by regulating EC basement membrane matrix assembly. Furthermore, we consider recent work showing that EC morphogenesis is balanced by a tendency for newly formed tubes to regress. This morphogenesis-regression balance is controlled by differential gene expression of such molecules as VEGF, angiopoietin-2, and PAI-1, as well as a plasmin-and matrix metalloproteinase-dependent mechanism that induces tube regression through degradation of ECM scaffolds that support EC-lined tubes. It is our hope that this review will stimulate increased interest and effort focused on the basic mechanisms regulating capillary tube formation and regression in 3D extracellular matrices. Anat Rec 268: 252-275, 2002.

Modeling lymphangiogenesis in a three-dimensional culture system

“…However, tube formation in these assay reflects the capacity to generate a complex plexus similar to that observed during embryogenesis 26 Our data confirmed the lymphangiogenic activity of PDGF-BB 9,23 , which could be abrogated by an inhibitor of PDGF receptor tyrosine kinase. Interestingly, blockade of the PDGF-receptor was sufficient to inhibit serum-stimulated lymphatic outgrowth.…”

Fluid Shear Stress and Sphingosine 1-Phosphate Activate Calpain to Promote Membrane Type 1 Matrix Metalloproteinase (MT1-MMP) Membrane Translocation and Endothelial Invasion into Three-dimensional Collagen Matrices

“…Angiogenesis is the formation of new blood vessels from pre-existing vessels and is required for development, wound healing, and pathological events (1)(2)(3)(4)(5). Endothelial cells (ECs) 2 in the vascular system must continually sense and respond to both biochemical and mechanical stimuli within their microenvironment to appropriately initiate angiogenesis.…”

Mechanotransduction in endothelial cell migration

“…Various ECM proteins bind to different integrins, and may activate different signaling molecules. For example, EC migration on collagen type I matrix is mediated by a 2 b 1 and a 1 b 1 integrins [Senger et al, 1997;Davis et al, 2000Davis et al, , 2002. Laminin, a major ECM protein in the basement membrane, preferentially binds to a 6 b 1 integrin in ECs [Sonnenberg et al, 1988].…”