University of Minnesota, Minneapolis, MN, USA.
J Mol Cell Cardiol. 2010 Aug;49(2):287-93. doi: 10.1016/j.yjmcc.2010.02.022. Epub 2010 Mar 4.
Heparan sulfate proteoglycans are abundant molecules in the extracellular matrix and at the cell surface. Heparan sulfate chains are composed of groups of disaccharides whose side chains are modified through a series of enzymatic reactions. Deletion of these enzymes alters heparan sulfate fine structure and leads to changes in cell proliferation and tissue development. The role of heparan sulfate modification has not been explored in the vessel wall. The goal of this study was to test the hypothesis that altering heparan sulfate fine structure would impact vascular smooth muscle cell (VSMC) proliferation, vessel structure, and remodeling in response to injury. A heparan sulfate modifying enzyme, N-deacetylase N-sulfotransferase1 (Ndst1) was deleted in smooth muscle resulting in decreased N- and 2-O sulfation of the heparan sulfate chains. Smooth muscle specific deletion of Ndst1 led to a decrease in proliferating VSMCs and the circumference of the femoral artery in neonatal and adult mice. In response to vascular injury, mice lacking Ndst1 exhibited a significant reduction in lesion formation. Taken together, these data provide new evidence that modification of heparan sulfate fine structure through deletion of Ndst1 is sufficient to decrease VSMC proliferation and alter vascular remodeling.
硫酸乙酰肝素蛋白聚糖是细胞外基质和细胞表面丰富的分子。硫酸乙酰肝素链由一组二糖组成，其侧链通过一系列酶反应进行修饰。这些酶的缺失改变了硫酸乙酰肝素的精细结构，导致细胞增殖和组织发育的变化。硫酸乙酰肝素修饰在血管壁中的作用尚未得到探索。本研究的目的是检验以下假设：改变硫酸乙酰肝素的精细结构会影响血管平滑肌细胞（VSMC）增殖、血管结构和损伤后的重塑。硫酸乙酰肝素修饰酶 N-去乙酰基 N-磺基转移酶 1（Ndst1）在平滑肌中缺失，导致硫酸乙酰肝素链的 N-和 2-O 磺化减少。平滑肌特异性缺失 Ndst1 导致新生和成年小鼠股动脉中增殖的 VSMC 数量减少和周长减小。在血管损伤后，缺乏 Ndst1 的小鼠的病变形成明显减少。总之，这些数据提供了新的证据，表明通过缺失 Ndst1 修饰硫酸乙酰肝素的精细结构足以减少 VSMC 增殖并改变血管重塑。
