The Role of Heparan Sulfate in Vascular Remodeling

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DESCRIPTION (provided by applicant): Heparan sulfate proteoglycans (HSPG) consist of a proteoglycan core protein covalently attached to heparan sulfate (HS) chains. These HS chains contain binding sites for numerous chemokines and growth factors. An emerging body of evidence suggests that specificity of chemokine and growth factor binding and activity is dependent upon the unique patterning of sulfated epitopes along the length of the HS chains. We have demonstrated that vascular injury invokes significant changes in the pattern of sulfated epitopes along the HS chains utilizing a sensitive state-of-the-art HPLC-based approach. These changes were accompanied by robust increases in the expression of enzymes that regulate HS sulfation. The initial sulfation reaction is catalyzed by a family of N-deacetylase-N-sulfotransferases (NDSTs). We identified a 20- fold increase in the most prevalent isoform, NDST1, following vascular injury in mice. The overall goal of this revised proposal is to establish the role of HS sulfation in vascular injury. To do this we will employ novel genetic murine models with targeted deletion of NDST1 in smooth muscle, and if necessary, additional targeted conditional deletions of enzymes that regulate HS sulfation and synthesis. A combination of genetic and biochemical approaches will be used in vivo and in vitro along with a newly established FACS-based approach to carefully define how HS sulfation influences the process of remodeling in response to injury. Specifically, we will: Test the hypothesis that decreasing HS sulfation leads to a reduction in lesion formation in response to injury. II. Test the hypothesis that decreasing HS sulfation impairs chemokine binding, expression, and activity. Understanding how the manipulation of HS structure and function in vivo affects vascular remodeling could have significant therapeutic value in treating vascular disease through the design of novel synthetic compounds that specifically modify HS. These studies will provide the first critical look at the impact of endogenous HS structure in vascular smooth muscle cells on the extent of injury and the regulation of chemokines.