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.