Role And Mechanism Of MIR-21 In The Expression Of Extracellular Matrix Of Vascular Smooth Muscle Cells In Response To Cyclic Strain

Vascular remodeling is the adaptive changes on vascular structure and function during organism growth, development, aging and disease. It has been investigated that cyclic strain plays a critical role in vascular remodeling, which is an essential pathology of many cardiovascular diseases, including hypertension and atherosclerosis. Hypertension is characterized by elevated cyclic strain, abnormal expression of extracellular matrix (ECM), which tells us that cyclic strain is associated with vascular remodeling. Therefore, mechanobiological mechanism by which cyclic strain induces vascular remodeling remains to be further explored.First, we established hypertensive rat model by narrowing the abdominal arota so as to learn about the effect of hypertensive state on expression of ECM in thoracic aorta of rats. We simulate the hypertensive state by cyclic strain, turning to investigate the mechanism about the effect of cyclic strain on the expression of ECM in vascular smooth muscle cells (VSMCs). Aortic VSMCs are subject to 0 (static state), 5% (physiological state) and 15%(hypertensive state)elongation and 1.25 Hz for 12 hours respectively by using Flexcercell 4000 Strain Unit. The expresson of Smad7, and ECM including collagen I, collagen III and elastin were detected by Western blotting. The expression of miR-21 was detected by Real-time RT-PCR. Finally, miR 21 inhibitor was used to study the role of miR21 in mechanical strain-induced expression of ECM.The main results are as follows:①Compared with the sham operation group, ECM and miR-21 in thoracic aorta of 2-week hypertesive group were significantly elevated;②Collagen I,collagen III and miR-21 in thoracic aorta of 4-week hypertensive group were significantly elevated; However, elastin was significantly decreased.③Compared with static group and 5% stretch group, the protein expression of collagen I did not show significant change. However, the protein expression of collagen III in VSMCs was significantly elevated. Whereas, the protein expression of elastin and Smad7 was significantly decreased in VSMCs. Cyclic stretch also enhanced miR-21 expression in VSMCs;④The protein expression of Collagen III was decreased, and Smad7 was increased by miR-21 downregulation via miR-21 inhibitor in VSMCs under static conditions or 15% cyclic stretch.Our results show that hypertension induced abnormal expression of ECM and resulted in the decrease of vascular compliance.Pathological cyclic strain also induced abnormal expression of ECM, pathological cyclic strain may affect Smad7 via miR-21, resulting in collagen III expression of extracellular matrix in VSMCs.Smad7 may be a new therapeutic target for vascular fibrosis.