Vascular Wall Microenvironment: Exosomes Secreted by Adventitial Fibroblasts Induced Vascular Calcification

Abstract

Abstract Vascular calcification often occurs in patients with chronic renal failure (CRF), which significantly increases the incidence of cardiovascular events in CRF patients. Our previous studies identified the crosstalk between the endothelial cells (ECs) and vascular smooth muscle cells (VSMCs), and the paracrine effect of VSMCs, which regulates the calcification of VSMCs. Herein, we aim to investigate the effects of exosomes secreted by high phosphorus (HPi) -induced adventitial fibroblasts (AFs) on the calcification of VSMCs, which will construct the novel theory of “Vascular Wall Microenvironment”. The conditioned medium of HPi-induced AFs promotes the calcification of VSMCs, which is partially abrogated by GW4869, a blocker of exosomes biogenesis or release. Exosomes secreted by high phosphorus-induced AFs (AFsHPi-Exos) show similar effects on VSMCs. miR-21-5p is enriched in AFsHPi-Exos, and miR-21-5p enhances osteoblast-like differentiation of VSMCs by downregulating Crim1 expression. AFsHPi-Exos and exosomes secreted by AFs with overexpression of miR-21-5p (AFsmiR21M-Exos) significantly accelerate vascular calcification in CRF mice. In general, the enriched miR-21-5p in AFsHPi-Exos promotes the calcification of VSMCs and vascular calcification by inhibiting the expression of cysteine-rich Crim1 protein (Crim1). Combined with our previous studies, the present experiment supports the theory of vascular wall microenvironment.