Yung Lai-Ming, Sánchez-Duffhues Gonzalo, Ten Dijke Peter, Yu Paul B
Division of Cardiology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA, USA.
Department of Molecular Cell Biology, Cancer Genomics Centre Netherlands, Leiden University Medical Center, Leiden, The Netherlands.
Cardiovasc Res. 2015 Nov 1;108(2):278-87. doi: 10.1093/cvr/cvv221. Epub 2015 Sep 25.
Vascular calcification contributes to mortality and morbidity in atherosclerosis, chronic kidney disease, and diabetes. Vascular calcific lesions contain osteoblast- and chondroblast-like cells, suggesting a process of endochondral or membranous ossification thought to result from the phenotypic plasticity of vascular cells. Bone morphogenetic protein (BMP) signalling potentiates atherosclerotic calcification, whereas BMP inhibition attenuates vascular inflammation and calcification in atherogenic mice. We hypothesized endothelial cells (ECs) may undergo osteogenic differentiation in response to BMP signalling and pro-atherogenic stimuli.
Among various BMP ligands tested, BMP6 and BMP9 elicited the most potent signalling in bovine aortic endothelial cells (BAEC), however, only BMP6 induced osteogenic differentiation. BMP6 and oxidized low-density lipoprotein (oxLDL) independently and synergistically induced osteogenic differentiation and mineralization, in a manner consistent with endothelial-to-mesenchymal transition. Treatment of ECs with BMP6 or oxLDL individually induced osteogenic and chondrogenic transcription factors Runx2 and Msx2, whereas treatment with BMP6 and oxLDL synergistically up-regulated Osterix and Osteopontin. Production of H2O2 was necessary for oxLDL-induced regulation of Runx2, Msx2, and Osterix in BAEC, and H2O2 was sufficient by itself to up-regulate these genes. Mineralization of ECs in response to BMP6 or oxLDL was abrogated by scavenging reactive oxygen species or inhibiting BMP type I receptor kinases. Similar synergistic effects of BMP and oxLDL upon osteogenic and chondrogenic transcription and phenotypic plasticity in human aortic endothelial cells were observed.
These findings provide a potential mechanism for the observed interactions of BMP signalling, oxidative stress, and inflammation in recruiting vascular calcification associated with atherosclerosis.
血管钙化会导致动脉粥样硬化、慢性肾病和糖尿病患者的死亡率和发病率升高。血管钙化病变中含有成骨细胞样细胞和软骨母细胞样细胞，提示存在软骨内成骨或膜内成骨过程，这一过程被认为是由血管细胞的表型可塑性导致的。骨形态发生蛋白（BMP）信号传导会增强动脉粥样硬化钙化，而抑制BMP则可减轻动脉粥样硬化小鼠的血管炎症和钙化。我们推测内皮细胞（ECs）可能会响应BMP信号传导和促动脉粥样硬化刺激而发生成骨分化。
在测试的各种BMP配体中，BMP6和BMP9在牛主动脉内皮细胞（BAEC）中引发的信号传导最强，然而，只有BMP6诱导了成骨分化。BMP6和氧化型低密度脂蛋白（oxLDL）分别独立且协同诱导成骨分化和矿化，其方式与内皮向间充质转化一致。单独用BMP6或oxLDL处理ECs会诱导成骨和软骨生成转录因子Runx2和Msx2，而用BMP6和oxLDL共同处理则会协同上调osterix和骨桥蛋白。H2O2的产生对于oxLDL诱导BAEC中Runx2、Msx2和osterix的调节是必需的，并且H2O2自身足以上调这些基因。通过清除活性氧或抑制BMP I型受体激酶，可消除ECs对BMP6或oxLDL的矿化反应。在人主动脉内皮细胞中也观察到了BMP和oxLDL对成骨和软骨生成转录及表型可塑性的类似协同作用。
这些发现为观察到的BMP信号传导、氧化应激和炎症在引发与动脉粥样硬化相关的血管钙化中的相互作用提供了一种潜在机制。
