Critical role of hyalurona derived from vascular smooth muscle cells after vascular injury in mice

用4-甲基伞形酮抑制HA合成可明显抑制损伤后新生内膜的形成。体外实验表明，低分子量透明质酸(LMW-HA)可诱导血管平滑肌细胞(VSMC)活化，包括迁移、增殖、炎性细胞因子和活性氧(ROS)的产生。VSMCs的迁移和增殖分别由CD44/RhoA和CD44/ERK1/2途径介导。由于HA合成酶2(HAS2)主要在损伤的动脉中表达，我们建立了在VSMCs中高表达小鼠HAS2基因的CTG小鼠(cHAS2/CreSM22α小鼠)，并表明HA过表达显著促进了袖带介导的血管损伤后新生内膜的形成。此外，从cHAS2/CreSM22pha小鼠分离的高表达HA的VSMCs显示出增强的迁移、增殖和炎性细胞因子和ROS的产生。

Inhibition of HA synthesis using 4-methylumbelliferone markedly inhibited neointimal formation after injury. In vitro experiments revealed that low-molecular-weight HA (LMW-HA) induced vascular smooth muscle cells (VSMC) activation, including migration, proliferation, and production of inflammatory cytokines and reactive oxygen species (ROS). The migration and proliferation of VSMCs were mediated by the CD44/RhoA and CD44/ERK1/2 pathways, respectively. Because HA synthase 2 (HAS2) is predominantly expressed in injured arteries, we generated cTg mice that overexpress the murine HAS2 gene specifically in VSMCs (cHAS2/CreSM22 alpha mice) and showed that HA overexpression markedly enhanced neointimal formation after cuff-mediated vascular injury. Further, HA-overexpressing VSMCs isolated from cHAS2/CreSM22alpha mice showed augmented migration, proliferation, and production of inflammatory cytokines and ROS.