Vascular smooth muscle cells (VSMC) are highly specialized, and exhibit a contractile phenotype when mature and fully differentiated, being responsible for vessel homeostasis and blood pressure control. In response to pro-atherogenic stimuli VSMC alter their state of differentiation, increase proliferation and migration, resulting in SMC phenotypes ranging from contractile to synthetic. This variability is observed in cell morphology and expression level of marker genes for differentiation status. There is growing evidence that bone morphogenetic protein (BMP) signaling is involved in vascular diseases, including atherosclerosis. Here, we evaluated in vitro the role of specific agonists/antagonists belonging to the BMP pathway on dedifferentiation of VSMC harvested during early stages of atherosclerosis.

Results

Comparing primary VSMC isolated from aortas of susceptible ApoE-/- animals fed 8 weeks of western diet with their littermate controls fed usual diet, we observed that recombinant BMP4 was able to reduce SM22-alpha and alpha actin gene expression indicating dedifferentiation was under way. Unexpectedly, treatment with recombinant Gremlin-1, a known BMP antagonist, also reduced 4–6.5 folds gene expression of SM22-alpha, alpha-actin and, calponin, exclusively in VSMC from ApoE-/- animals, independently on the diet consumed.

Conclusion

Our data show that BMP4 is capable of modulating of SM22-alpha and alpha actin gene expression, indicative of cell dedifferentiation in VSMC. Additionally, we report for first time that Gremlin-1 acts independently of the BMP pathway and selectively on VSMC from susceptible animals, reducing the expression of all genes evaluated.

中文翻译：

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Gremlin-1增强了动脉粥样硬化早期阶段VSMC的去分化

血管平滑肌细胞（VSMC）是高度专业化的，成熟并完全分化后会表现出收缩表型，负责血管的稳态和血压控制。响应促动脉粥样硬化刺激，VSMC改变其分化状态，增加增殖和迁移，从而导致SMC表型从收缩到合成。在细胞形态和用于分化状态的标记基因的表达水平中观察到了这种可变性。越来越多的证据表明，骨形态发生蛋白（BMP）信号传导与包括动脉粥样硬化在内的血管疾病有关。在这里，我们评价体外时动脉粥样硬化的早期阶段，属于对VSMC的分化的BMP途径特定激动剂/拮抗剂的作用收获。

结果

比较从喂食西部饮食8周的易感ApoE-/-动物的主动脉分离的原代VSMC与喂食普通饮食的同窝幼仔对照，我们观察到重组BMP4能够降低SM22-α和α肌动蛋白基因表达，表明去分化正在进行中。出乎意料的是，使用重组的Gremlin-1（一种已知的BMP拮抗剂）进行治疗，也仅在ApoE-/-动物的VSMC中使SM22-α，α-肌动蛋白和钙蛋白的基因表达降低了4-6.5倍，而与饮食无关。

结论

我们的数据表明BMP4能够调节SM22-alpha和alpha肌动蛋白基因表达，这表明VSMC中的细胞去分化。此外，我们首次报告Gremlin-1的行为独立于BMP途径，并选择性地作用于易感动物的VSMC，从而降低了所有评估基因的表达。