Hyaluronan negatively regulates vascular calcification involving BMP2 signaling
Hyaluronan negatively regulates vascular calcification involving BMP2 signaling
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透明质酸通过 BMP2 信号传导负向调节血管钙化
DOI：
10.1038/s41374-018-0076-x
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发表时间：
2018-10-01
影响因子：
5
通讯作者：
Yan, Jianyun
中科院分区：
文献类型：
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作者：
Kong, Yonglun;Liang, Qingchun;Yan, Jianyun
血管钙化是一个高度调节的生物学过程，类似于骨形成，涉及血管平滑肌细胞（VSMCs）的成骨分化。透明质酸（HA），软骨细胞外基质的主要结构成分，已被证明能抑制成骨细胞分化。然而，HA是否影响VSMCs的成骨分化和钙化仍不清楚。在本研究中，我们使用体外和离体血管钙化模型来研究HA在血管钙化中的作用。通过茜素红染色和钙含量测定，高分子量和低分子量HA处理均以剂量依赖性方式显着减少大鼠VSMC的钙化。离体研究进一步证实了HA对血管钙化的抑制作用。类似地，HA处理降低ALP活性和骨相关分子（包括Runx 2、BMP 2和Msx 2）的表达。相反，4-甲基伞形酮（4 MU）抑制HA合成促进大鼠VSMCs钙化。此外，腺病毒介导的VSMC中主要HA合酶HA合酶2（HAS 2）的过表达也抑制了VSMC的钙化，而CRISPR/Cas9介导的HAS 2敲除促进了大鼠A10细胞的钙化。此外，我们还发现HA处理后VSMCs中BMP 2信号被抑制。重组BMP 2增强高钙和高磷诱导的VSMC钙化，这可以被HA治疗阻断。总之，这些发现表明HA抑制涉及BMP 2信号传导的血管钙化。
Vascular calcification is a highly regulated biological process similar to bone formation involving osteogenic differentiation of vascular smooth muscle cells (VSMCs). Hyaluronan (HA), a major structural component of the extracellular matrix in cartilage, has been shown to inhibit osteoblast differentiation. However, whether HA affects osteogenic differentiation and calcification of VSMCs remains unclear. In the present study, we used in vitro and ex vivo models of vascular calcification to investigate the role of HA in vascular calcification. Both high and low molecular weight HA treatment significantly reduced calcification of rat VSMCs in a dose-dependent manner, as detected by alizarin red staining and calcium content assay. Ex vivo study further confirmed the inhibitory effect of HA on vascular calcification. Similarly, HA treatment decreased ALP activity and expression of bone-related molecules including Runx2, BMP2 and Msx2. By contrast, inhibition of HA synthesis by 4-methylumbelliferone (4MU) promoted calcification of rat VSMCs. In addition, adenovirus-mediated overexpression of HA synthase 2 (HAS2), a major HA synthase in VSMCs, also inhibited calcification of VSMCs, whereas CRISPR/Cas9-mediated HAS2 knockout promoted calcification of rat A10 cells. Furthermore, we found that BMP2 signaling was inhibited in VSMCs after HA treatment. Recombinant BMP2 enhanced high calcium and phosphate-induced VSMC calcification, which can be blocked by HA treatment. Taken together, these findings suggest that HA inhibits vascular calcification involving BMP2 signaling.