Between molecules and morphology. Extracellular matrix and creation of vascular form

In response to an angiogenic stimulus, ECs initiate programs of gene expression that result in the quantitative alteration of gene products within nuclear, cytoplasmic, cell surface, and extracellular compartments. During the formation of new microvasculature, patterns of molecular expression among individual ECs must direct the creation of complex, multicellular morphologies in two and three dimensions. Studies in vitro indicate that cell-generated forces of tension can organize ECM into structures that direct the behavior of single cells (via influences on cellular elongation, alignment, and migration) and that provide positional information for the creation of multicellular patterns. Significantly, the formation of organized matrical structures is controlled by gene products (of ECs or other cell types that populate the ECM) that influence the balance between the forces of cellular tension and the viscoelastic resistance of the ECM. Regulation of relevant genes could be accomplished by soluble molecular signals (eg, growth factors) and/or solid-state signals arising from specific arrangements of cytoskeletal structure that, in turn, are a function of the equilibrium between cellular tension and matrical resistance. Within cells, information for the construction of complex organelles is encoded in the shapes of the constituent molecules. Similarly, the creation of complex vascular architecture must be mediated by molecular shapes, a fact that is readily apparent in simple receptor-ligand interactions such as the binding of growth factors to ECs or the attachment of ECs to one another. However, between molecules and morphology also exists a set of multilayered, interactive, multimolecular systems that establish vascular form at unicellular and multicellular levels. Characterization of these systems is an elusive target that resides at the frontier of vascular biology; the identification of models in vitro that accurately reproduce macroscale events of vascular morphogenesis should advance considerably our understanding of vascular development and lead to an elucidation of its regulation in vivo.