Abstract
Objective: Stem cell-derived extracellular vesicles are decreased with aging. Aging is a major risk factor for the development of arterial stiffness and hypertension. This study was designed to assess the effect of inducible pluripotent stem cells (iPSC)-derived extracellular vesicles (EVs) on the aging-related arterial stiffness and hypertension. Methods and Results: Adult (6 months) and aged (20 months) mice were used. Pulse wave velocity (PWV), an index of arterial stiffness and blood pressure were measure twice a week. PWV and blood pressure were increased significantly in aged mice, indicating arterial stiffness and hypertension. One of the exciting findings is that intravenous administration of iPSC-derived EVs significantly decreased aging-related arterial stiffness and hypertension. Treatment with EVs also enhanced endothelium-dependent vascular relaxation and arterial compliance in aged mice. It was noticed that elastin degradation and collagen I deposition (fibrosis) were increased in aortas of aged mice, formulating a structural basis of arterial stiffness. The aging-associated structural remodeling was nearly eliminated by EVs. Mechanistically, EVs abolished downregulation of Sirt1 and eNOS protein expression in aortas of aged mice. In cultured human aortic endothelial cells, we found that EVs promoted the expression and phosphorylation of Sirt1, AMPKα, and eNOS. In addition, EVs attenuated aging-associated renal glomerulosclerosis and tubulointerstitial fibrosis. Conclusion: This study demonstrates for the first time that iPSC-derived EVs improved aging-associated vascular endothelial dysfunction, arterial stiffening, renal remodeling and hypertension likely via regulating the Sirt1-AMPKα-eNOS pathway. A decrease in stem cell-derived EVs plays an important role in aging-associated arterial stiffening and hypertension. This finding sheds light on the therapeutic potential of EVs for arterial stiffness and hypertension associated with aging.
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