Heparanase alters arterial structure, mechanics, and repair following endovascular stenting in mice.
Heparanase alters arterial structure, mechanics, and repair following endovascular stenting in mice.
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DOI：
10.1161/circresaha.108.180695
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发表时间：
2009-02-13
影响因子：
20.1
通讯作者：
Edelman ER
中科院分区：
文献类型：
--
作者：
Baker AB;Groothuis A;Jonas M;Ettenson DS;Shazly T;Zcharia E;Vlodavsky I;Seifert P;Edelman ER
硫酸肝素蛋白聚糖（HSPGs）是血管重塑和修复的有效调节剂。肝素酶是哺乳动物细胞中能够降解硫酸肝素的主要酶。在这里，我们研究了肝素酶在控制动脉结构、力学和重塑中的作用。体外研究支持内皮细胞中肝素酶的表达作为血管平滑肌细胞（vSMC）增殖的内皮抑制的负调节因子。肝素酶的表达也改变了动脉结构和损伤后的重塑。过表达肝素酶的转基因小鼠动脉厚度、细胞密度和机械顺应性均增加。Zucker大鼠血管内支架植入研究表明，与瘦大鼠相比，肥胖、高脂血症大鼠的新生内膜中肝素酶表达增加。肝素酶在新生内膜内的表达程度与损伤后新生内膜的厚度密切相关。为了测试肝素酶过表达对动脉修复的影响，我们建立了一种新型的小鼠支架损伤模型，使用小直径自膨胀支架。通过该模型，我们发现在过表达肝素酶的转基因小鼠中，新内膜形成和巨噬细胞募集增加。综上所述，这些结果支持肝素酶在动脉结构、力学和修复中的调节作用。
Heparan sulfate proteoglycans (HSPGs) are potent regulators of vascular remodeling and repair. Heparanase is the major enzyme capable of degrading heparan sulfate in mammalian cells. Here we examined the role of heparanase in controlling arterial structure, mechanics and remodeling. In vitro studies supported that heparanase expression in endothelial cells serves as a negative regulator of endothelial inhibition of vascular smooth muscle cell (vSMC) proliferation. Arterial structure and remodeling to injury were also modified by heparanase expression. Transgenic mice overexpressing heparanase had increased arterial thickness, cellular density and mechanical compliance. Endovascular stenting studies in Zucker rats demonstrated increased heparanase expression in the neointima of obese, hyperlipidemic rats in comparison to lean rats. The extent of heparanase expression within the neointima strongly correlated with the neointimal thickness following injury. To test the effects of heparanase overexpression on arterial repair, we developed a novel murine model of stent injury using small diameter self-expanding stents. Using this model we found that increased neointimal formation and macrophage recruitment occurs in transgenic mice overexpressing heparanase. Taken together, these results support a role for heparanase in the regulation of arterial structure, mechanics and repair.