This Bioengineering Research Partnership assembles a team led by two biomedical engineers and a molecular physiologist to focus on the integrative control of vascular pattern formation. While vascular assembly and pattern formation will be needed as critical elements of successful therapeutic collateralization of progressively ischemic organs and in tissue engineering of various tissue substitutes in the future, remarkably little is known of the cells involved, the array of signal molecules and their genetic regulation, and the biophysical factors regulating the spatial and temporal dynamics of vascular pattern formation. Key questions now are: what is the origin of cells responsible for the investment of arterioles with contractile cells and what are the signals that control their proliferation, migration, and differentiation? An integrative systems approach is proposed to measure the dynamics of arteriolar pattern formation in vivo across time scales from the embryo to the adult, and spanning spatial scales from genes to cells to whole networks, and to create a new generation of computational approaches to understand the complex interplay of multiple interacting cells and signal molecules.
The specific aims are 1) to determine the role of PDGF and TGF-beta in arteriolar pattern formation during embryonic development, 2) to determine the cell types involved, role of PDGF and TGF-beta signaling, and spatial and temporal patterns of arteriolar assembly in adults, and 3) to develop and use a new cell-based computer simulation to perform integrative spatio-temporal analysis of the arterialization process in the embryo and adult, including multi-signal control of fibroblast and smooth muscle cell proliferation, migration, and differentiation. The multidisciplinary team will utilize unique gene-targeted mice in conjunction with innovative in vivo measurements, and integration of the data into the new computational models will improve understanding of the gene circuitry regulating arteriolar pattern formation. This focused partnership with three investigators who have worked together previously brings a unique set of complementary tools to bear on the problem. Year 1 milestones are to obtain the first microvessel mappings of contractile cell recruitment in transgenic mouse embryonic tissues, to implement spatial guidance of arteriolar pattern formation through application of focal growth factors in adult window chambers, and to implement a novel computational model of arterialization that represents smooth muscle cells and fibroblasts discretely. The long term goal is to define the mechanisms that control arteriolar pattern formation, and to provide the basis for powerful therapeutic vascularization procedures that function in the native environment in vivo.
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