The Grifola frondosa-derived ACE inhibitory peptide attenuated the exosomes-mediated phenotype transformation of vascular smooth muscle cells

• The Grifola frondosa -derived hydrolysates by ethanol could prepare alcohol soluble small peptides with high ACE inhibitory activity. • The GFP ameliorated Ang II-induced phenotypic transformation of VSMCs by regulating ACE, OPN, and a-SMA expression. • The exosomes from Ang II-induced VSMCs converted the phenotype of VSMCs to a synthetic phenotype accompanied by inflammation. • GFP-induced VSMCs-derived exosomes improved phenotypic switching and inflammatory response of VSMCs. Grifola frondosa , a high-protein edible mushroom, exhibited potential antihypertensive effects through ACE inhibition. The ACE was expressed in vascular smooth muscle cells (VSMCs) and transported via exosomes. This study prepared low molecular weight GFP through enzymatic hydrolysis, showing strong ACE inhibition. Ang II increased ACE expression and activity in VSMCs, inducing phenotype switching by up-regulating α-SMA and OPN. GFP reduced Ang II’s stimulating effects. Exosomes from Ang II-treated (Ang II-Exos) or GFP-treated (GFP-Exos) VSMCs had particle sizes under 200 nm with positive biomarkers CD63 and Tsg101. Co-culture experiments revealed higher ACE loading in Ang II-Exos than in VSMCs, but significantly lower in GFP-Exos. Ang II-Exos promoted VSMC proliferation, migration, inflammation, and phenotypic switching, while GFP-Exos significantly reduced these effects by inhibiting ACE activity and regulating the NF-κB pathway. GFP effectively mitigated Ang II-induced VSMC dysfunction by modulating exosome-mediated ACE loading and phenotypic transformation.