Department of Geriatrics, Fujian Key Laboratory of Vascular Aging (Fujian Medical University), Fujian Clinical Research Center for Senile Vascular Aging and Brain Aging, Fujian Medical University Union Hospital, Fuzhou, China.
Gerontology. 2024;70(8):858-875. doi: 10.1159/000539399. Epub 2024 Jun 1.
INTRODUCTION: 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. CONCLUSION: 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.
简介：高血压可加速和加重动脉老化和钙化过程。然而，其背后的机制尚未得到很好的阐明。
方法：在这里，我们监测了自发性高血压大鼠（SHR）主动脉和胸主动脉血管平滑肌细胞（VSMCs）中纤连蛋白（FN）/α5 整联蛋白、骨形态发生蛋白 2/基质 Gla 蛋白（BMP2/MGP）和 Runx2 的动态变化，以及 VSMCs 在动脉老化和钙化过程中的表型转化。此外，还通过分子水平的拮抗剂实验研究了动脉老化和钙化。
结果：我们发现，在衰老过程中，SHR 中动脉老化和钙化与细胞外 FN 及其 α5 整联蛋白受体表达呈正相关，体外 SHR 的 VSMCs 也是如此。整联蛋白受体抑制剂 GRGDSP 会延迟这一动脉老化和钙化过程。此外，升高的 FN 和 α5 整联蛋白受体表达引起了 BMP2/MGP 的失衡，其中强力成骨诱导剂 BMP2 的表达增加，而钙化抑制剂 MGP 的表达减少。此外，这伴随着 Runx2 的上调和 VSMCs 从收缩表型向成骨样细胞的表型转化。值得注意的是，BMP2 拮抗剂 rmNoggin 足以改善 VSMCs 的老化和钙化过程，而外源性 BMP2 添加则加速和聚集了这一过程。
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中 FN 及其高结合亲和力的α5 整联蛋白受体的结果，这反过来又加重了 BMP2/MGP 的失衡，促进了 Runx2 的转录，并诱导了 VSMCs 从收缩表型向成骨样细胞的表型转化。我们的研究将为高血压相关的动脉老化和钙化提供新的见解，并为动脉钙化的控制提供新的思路，特别是对那些患有高血压的患者。
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