背景:高血压可加速和加重动脉老化和钙化的过程。然而,背后的机制尚未得到很好的阐明。
方法:这里,我们监测了纤维连接蛋白(FN)/α5整合素的动态变化,骨形态发生蛋白2/基质Gla蛋白(BMP2/MGP)和Runx2在自发性高血压大鼠(SHR)主动脉和胸主动脉血管平滑肌细胞(VSMC)中的表达,也是动脉老化和钙化过程中VSMCs的表型转化。Further,通过分子水平的拮抗剂实验对动脉老化和钙化的研究进行了探索。
结果:我们发现细胞外FN及其α5整合素受体的表达与SHR衰老过程中的动脉衰老和钙化呈正相关,在体外SHR的VSMC中也是如此。GRGDSP的整合素受体抑制剂将延迟这种动脉老化和钙化过程。此外,FN和α5整合素受体表达升高引起BMP2/MGP的不平衡,其中BMP2的表达,一种有效的成骨诱导剂,当MGP增加时,钙化抑制剂,decreased.此外,随后是Runx2的上调和VSMC从收缩表型向成骨细胞样细胞的表型转化.值得注意的是,rmNoggin的BMP2拮抗剂足以改善VSMC的老化和钙化过程,外源BMP2的添加加速和聚集了该过程。
结论:我们的研究表明,高血压相关的动脉老化和钙化可能是高血压上调主动脉壁FN及其高结合亲和力整合素α5受体的结果,这反过来又加剧了BMP2/MGP的不平衡,促进Runx2的转录,并诱导VSMC从收缩表型转化为成骨细胞样细胞。我们的研究将为高血压相关的动脉老化和钙化提供见解,并为动脉钙化的控制提供新的思路。尤其是那些有高血压的人。
BACKGROUND: Hypertension can accelerate and aggravate the process of arterial ageing and calcification. However, the mechanism behind has yet to be well elucidated.
METHODS: Here, we monitored the dynamic changes of fibronectin (FN)/α5 integrin, bone morphogenetic protein 2/matrix Gla protein (BMP2/MGP), and Runx2 in the aorta of spontaneously hypertensive rats (SHRs) and thoracic aortic vascular smooth muscle cells (VSMCs), also the phenotypic transformation of VSMCs during the process of arterial ageing and calcification. Further, study on arterial ageing and calcification through antagonist experiments at the molecular level was explored.
RESULTS: We found extracellular FN and its α5 integrin receptor expressions were positively associated with arterial ageing and calcification in SHR during ageing, as well in VSMCs from SHR in vitro. Integrin receptor inhibitor of GRGDSP would delay this arterial ageing and calcification process. Moreover, the elevated FN and α5 integrin receptor expression evoked the disequilibrium of BMP2/MGP, where the expression of BMP2, a potent osteogenic inducer, increased while MGP, a calcification inhibitor, decreased. Furthermore, it was followed by the upregulation of Runx2 and the phenotypic transformation of VSMCs from the contractile phenotype into the osteoblast-like cells. Notably, BMP2 antagonist of rmNoggin was sufficient to ameliorate the ageing and calcification process of VSMCs and exogenous BMP2-adding accelerate and aggregate the process.
CONCLUSIONS: Our study revealed that hypertension-associated arterial ageing and calcification might be a consequence that hypertension up-regulated FN and its high binding affinity integrin α5 receptor in the aortic wall, which in turn aggravated the imbalance of BMP2/MGP, promoted the transcription of Runx2, and induced the phenotypic transformation of VSMCs from the contractile phenotype into the osteoblast-like cells. Our study would provide insights into hypertension-associated arterial ageing and calcification and shed new light on the control of arterial calcification, especially for those with hypertension.