Perivascular adipose tissue–derived extracellular vesicle miR‐221‐3p mediates vascular remodeling

Adipose tissue–secreted extracellular vesicles (EVs) containing microRNAs (miRNAs) convey intercellular message signaling. The biogenesis of EV‐miRNAs from perivascular adipose tissue (PVAT) and their roles in intercellular communication in response to obesity‐associated inflammation have not yet been fully explored. By feeding mice a high‐fat diet for 16 wk, we established obesity‐associated, chronic low‐grade inflammation in PVAT, characterized as hypertrophy of perivascular adipocytes, decreased adipogenesis, and proinflammatory macrophage infiltration. We show that PVAT‐derived EVs and their encapsulated miRNAs can be taken up into vascular smooth muscle cells (VSMCs) in vivo and in vitro . miR‐221‐3p is one of the highly enriched miRNAs in obese PVAT and PVAT‐derived EVs. Transfer and direct overexpression of miR‐221‐3p dramatically enhances VSMC proliferation and migration. Peroxisome proliferator–activated receptor γ coactivator 1α is identified as a miR‐221‐3p target in VSMC phenotypic modulation. Obese mice secrete abundant miRNA‐containing EVs, evoking inflammatory responses in PVAT and vascular phenotypic switching in abdominal aorta of lean mice. Local delivery of miR‐221‐3p mimic in femoral artery causes vascular dysfunction by suppressing the contractile genes in the arterial wall. Our findings provide an EV–miR‐221‐3p–mediated mechanism by which PVAT triggers an early‐stage vascular remodeling in the context of obesity‐associated inflammation.—Li, X., Ballantyne, L. L., Yu, Y., Funk, C. D. Perivascular adipose tissue–derived extracellular vesicle miR‐221‐3p mediates vascular remodeling. FASEB J. 33, 12704–12722 (2019). www.fasebj.org