The crosstalk between endothelial cells and vascular smooth muscle cells aggravates high phosphorus-induced arterial calcification

Abstract

Arterial calcification is highly prevalent, particularly in patients with end-stage renal disease (ESRD). The osteogenic differentiation of vascular smooth muscle cells (VSMCs) is the critical process for the development of arterial calcification. However, the detailed mechanism of VSMCs calcification remains to be elucidated. Here, we investigated the role of exosomes (Exos) derived from endothelial cells (ECs) in arterial calcification and its potential mechanisms in ESRD. Accelerated VSMCs calcification was observed when VSMCs were exposed to ECs culture media stimulated by uremic serum or high concentration of inorganic phosphate (3.5 mM Pi). and the pro-calcification effect of the ECs culture media was attenuated by exosome depletion. Exosomes derived from high concentrations of inorganic phosphate-induced ECs (ECsHPi-Exos) could be uptaken by VSMCs and promoted VSMCs calcification. Microarray analysis showed that miR-670-3p was dramatically increased in ECsHPi-Exos compared with exosomes derived from normal concentrations of inorganic phosphate (0.9 mM Pi) induced ECs (ECsNPi-Exos). Mechanistically, insulin-like growth factor 1 (IGF-1) was identified as the downstream target of miR-670-3p in regulating VSMCs calcification. Notably, ECs-specific knock-in of miR-670-3p of the 5/6 nephrectomy with a high-phosphate diet (miR-670-3pEC-KI + NTP) mice that upregulated the level of miR-670-3p in artery tissues and significantly increased artery calcification. Finally, we validated that the level of circulation of plasma exosomal miR-670-3p was much higher in patients with ESRD compared with healthy controls. Elevated levels of plasma exosomal miR-670-3p were associated with a decline in IGF-1 and more severe artery calcification in patients with ESRD. Collectively, these findings suggested that ECs-derived exosomal miR-670-3p could promote arterial calcification by targeting IGF-1, which may serve as a potential therapeutic target for arterial calcification in ESRD patients.

Vascular calcification in CKD: New insights into its mechanisms

“…In addition, given their location in the innermost layer of the blood vessel lumen and preferential reception of various pro‐calcifying stimuli, ECs can pass messages to vascular wall cells and communicate with them. Crosstalk between ECs and VSMCs via cytokines through a paracrine mechanism, extracellular vesicles (Freise et al, 2021; X. Lin et al, 2022), MiRNAs and myoendothelial gap junctions also plays a role in VC. Although progress has been made in understanding the multicellular communication during VC, it is still largely assumptive and needs to be clarified.…”

Role of nutritional vitamin D in chronic kidney disease-mineral and bone disorder: A narrative review

“…[ 15 ] Endothelial cell-derived exosomal miR-670-3p can promote arterial calcification by targeting insulin-like growth factor-1, which may be a potential therapeutic target for arterial calcification in hemodialysis patients. [ 16 ]…”

“…[15] Endothelial cell-derived exosomal miR-670-3p can promote arterial calcification by targeting insulin-like growth factor-1, which may be a potential therapeutic target for arterial calcification in hemodialysis patients. [16] There is a close relationship between vascular calcification and osteoporosis in CKD patients. [17] Vascular smooth muscle cells and bone morphogenetic cells are derived from the same mesenchymal stem cell line.…”

Cold Exposure Attenuates Medial Arterial Calcification via Autophagy

“…Calci cation of the major arteries is an important phenotype of vascular ageing. Researchers have found that exosomes play different roles in MAC [20][21][22]. Exosomes may serve as communication vesicles and mediate vascular calci cation at ambient temperature.…”