Department of Anatomy, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
Commun Biol. 2022 Apr 19;5(1):364. doi: 10.1038/s42003-022-03313-z.
Vascular calcification occurs in arterial aging, atherosclerosis, diabetes mellitus, and chronic kidney disease. Transforming growth factor-β1 (TGF-β1) is a key modulator driving the osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs), leading to vascular calcification. We hypothesize that milk fat globule-epidermal growth factor 8 (MFG-E8), a glycoprotein expressed in VSMCs, promotes the osteogenic transdifferentiation of VSMCs through the activation of TGF-β1-mediated signaling. We observe that the genetic deletion of MFG-E8 prevents calcium chloride-induced vascular calcification in common carotid arteries (CCAs). The exogenous application of MFG-E8 to aged CCAs promotes arterial wall calcification. MFG-E8-deficient cultured VSMCs exhibit decreased biomineralization and phenotypic transformation to osteoblast-like cells in response to osteogenic medium. MFG-E8 promotes β1 integrin-dependent MMP2 expression, causing TGF-β1 activation and subsequent VSMC osteogenic transdifferentiation and biomineralization. Thus, the established molecular link between MFG-E8 and vascular calcification suggests that MFG-E8 can be therapeutically targeted to mitigate vascular calcification.
血管钙化发生于动脉老化、动脉粥样硬化、糖尿病和慢性肾脏病中。转化生长因子-β1（TGF-β1）是驱动血管平滑肌细胞（VSMCs）成骨分化，导致血管钙化的关键调节因子。我们假设在 VSMCs 中表达的乳脂肪球表皮生长因子 8（MFG-E8）通过激活 TGF-β1 介导的信号通路促进 VSMCs 的成骨分化。我们观察到，MFG-E8 的基因缺失可预防氯化钙诱导的颈总动脉（CCAs）血管钙化。外源性 MFG-E8 应用于老年 CCAs 可促进动脉壁钙化。MFG-E8 缺乏的培养 VSMCs 在成骨培养基中表现出生物矿化减少和向成骨样细胞的表型转化减少。MFG-E8 促进β1 整合素依赖性 MMP2 表达，导致 TGF-β1 激活，随后 VSMC 成骨分化和生物矿化。因此，MFG-E8 与血管钙化之间建立的分子联系表明，MFG-E8 可以作为治疗靶点来减轻血管钙化。
