While angiogenesis represents an important element of tissue response to ischemia or wounding and tumor-stimulated neovascularization plays a critical role in cancer's growth and expansion. At the same time relatively little new vessel growth takes place in most adult tissues including the myocardium. Although regulation of angiogenic response is an important part of normal and pathological homeostasis, little is known about the mechanisms of this control. One such control mechanism may involve the heparan sulfate matrix. Heparan sulfate proteoglycans (HSPG) can mediate both heparin- binding growth factor-receptor interaction at the cell surface as well as accumulation and storage of these growth factors in the extracellular matrix. Therefore any alteration of heparan sulfate composition on the cell surface or in the extracellular matrix can affect growth factor signaling. Recent observations have suggested that heparan sulfate chain carrying core proteins, in particular, syndecan-4, may play an important role in outside-in signaling by activating specific PKC isoenzymes and participating in PDZ domain-mediated assembly of intracellular protein complexes. In this grant application, we propose to explore these issues in the context of angiogenesis. In particular, we will study the effect of alterations in expression of heparan sulfate-carrying proteins in endothelial cells on functional properties of these cells in vitro and in vivo and investigate mechanisms responsible for these effects. It is hoped that better understanding of core protein/heparan sulfate chains control of endothelial cell function will provide new insights into the regulation of angiogenesis.
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