EXTRACELLULAR MATRIX GUIDANCE OF CAPILLARY SPROUTING

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it is well known that angiogenesis is a critical component of many normal and pathological conditions, including muscle adaptation to exercise, myocardial adaptation to ischemia, tumor development, and wound healing. Typically, new blood vessels form by sprouting from pre-existing capillaries or small venules in the microvascular network. It has been shown that a periocyte-like, non-endothelial cell lacking VEGF receptors guides capillary sprouts from pre-existing microvessels in rat connective tissue. This pericytic guide cell migrates on a microfibril matrix in vivo and produces a second provisional matrix that may be a scaffolding for endothelial cells in the proximal portion of the sprout. This proposal consists of three specific aims that are designed to better elucidate the role that the pericytic leader cell, the microfibril network, and the secondary matrix produced by the pericytic guide cell play in capillary sprouting. The first specific aim is to better characterize the spatial expression of selected extracellular matrix proteins, integrins, growth factors, and growth factor receptors in the capillary sprout and surrounding tissue region in mesenteric networks undergoing spontaneous angiogenesis and angiogenesis in response to wound healing, inflammation, and hypoxia. The second specific aim will utilize an innovative in vivo approach to analyzing the migration of pericytic guide cells and endothelial cells on the underlying matrix in response to the application of selected growth factors (VEGF, bFGF, PDGF-BB, TGFbeta). Here, direct observations of matrix guided cell migration or native extracellular matrix will be made in vivo, thereby identifying which growth factors are capable of acting as chemoattractants during matrix guided capillary sprouting. 'The third specific aim is to investigate the impact that disrupting selected ECM-integrin interactions has on capillary sprout composition and structure, microvascular development and density and network patterning. The long term goal of this project is to understand the molecular interactions that must occur betweer the pericyte-like leader cells, the extracellular matrix, and the endothelial cells to produce capillary sprouting that leads to the formation of a functional microvascular network. By better understanding the cells and molecular signals that are essential for this essential process, we may eventually be able to, 1) find better targets for interventional anti-angiogenesis therapy, 2 find better targets for stimulating angiogenesis in ischemic tissues, and 3) tissue engineer extracellular matrix substrates the support the formation of functional microvascular networks in vivo.