Abstract:
Vascular smooth muscle cells (VSMCs) play a key role in aortic aneurysm formation. Bone morphogenetic proteins (BMPs) have been implicated as important regulators of VSMC phenotype, and dysregulation of the BMP pathway has been shown to be associated with vascular diseases. The aim of this study was to investigate for the first time the effects of BMP-4 on the VSMC phenotype and to understand its role in the development of thoracic aortic aneurysms (TAAs). Using the angiotensin II (AngII) osmotic pump model in mice, aortas from mice with VSMC-specific BMP-4 deficiency showed changes similar to AngII-infused aortas, characterised by a loss of contractile markers, increased fibrosis, and activation of matrix metalloproteinase 9. When BMP-4 deficiency was combined with AngII infusion, there was a significantly higher rate of apoptosis and aortic dilatation. In vitro, VSMCs with mRNA silencing of BMP-4 displayed a dedifferentiated phenotype with activated canonical BMP signalling. In contrast, BMP-2-deficient VSMCs exhibited the opposite phenotype. The compensatory regulation between BMP-2 and BMP-4, with BMP-4 promoting the contractile phenotype, appeared to be independent of the canonical signalling pathway. Taken together, these results demonstrate the impact of VSMC-specific BMP-4 deficiency on TAA development.
摘要:
血管平滑肌细胞(VSMC)在主动脉瘤形成中起关键作用。骨形态发生蛋白(BMPs)被认为是VSMC表型的重要调节因子,BMP通路的失调已被证明与血管疾病相关。这项研究的目的是首次研究BMP-4对VSMC表型的影响,并了解其在胸主动脉瘤(TAAs)发展中的作用。使用小鼠血管紧张素II(AngII)渗透泵模型,来自具有VSMC特异性BMP-4缺陷的小鼠的主动脉显示出与输入AngII的主动脉相似的变化,以收缩标记丢失为特征,纤维化增加,和激活基质金属蛋白酶9。当BMP-4缺乏与AngII输注相结合时,凋亡率和主动脉扩张率明显较高。体外,具有BMP-4的mRNA沉默的VSMC显示具有激活的典型BMP信号传导的去分化表型。相比之下,BMP-2缺陷型VSMC表现出相反的表型。BMP-2和BMP-4之间的代偿调节,BMP-4促进收缩表型,似乎独立于规范的信号通路。一起来看,这些结果表明VSMC特异性BMP-4缺乏对TAA发展的影响。