The Protective Effects of Tripeptides VPP and IPP against Small Extracellular Vesicles from Angiotensin II-Induced Vascular Smooth Muscle Cells Mediating Endothelial Dysfunction in Human Umbilical Vein Endothelial Cells

Abstract

Endothelial dysfunction is a common disorder of vascular homeostasis in hypertension characterized by oxidative stress, malignant migration, inflammatory response, and active adhesion response of endothelial cells. The extracellular vesicles (EVs), a vital participant in vascular cell communication, have been considered responsible for vascular disease progression. However, the potential mechanism of antihypertensive peptides against the EVs-induced endothelial dysfunction is still unclear. In this study, we investigated whether the antihypertensive peptides Val-Pro-Pro (VPP) and Ile-Pro-Pro (IPP) ameliorate the effects of EVs from Ang II-induced vascular smooth muscles (VSMCs) on the endothelial dysfunction. The dihydroethidium staining, wound healing assay, 3D cell culture, and co-culture with U937 monocyte were used to investigate the oxidant/antioxidant balance, migration, tube formation, and cell adhesion in EV-induced human umbilical vein endothelial cells. VPP and IPP treatment reduced the level of reactive oxygen species and EV-induced expression of adhesion molecules and restored the ability of tube formation by upregulating endothelial nitric oxide synthase expression. VPP and IPP reduced the protein levels of IL-6 to 227.34 ± 10.56 and 273.84 ± 22.28 pg/mL, of IL-1β protein to 131.56 ± 23.18 and 221.14 ± 13.8 pg/mL, and of MCP-1 to 301.48 ± 19.75 and 428.68 ± 9.59 pg/mL. These results suggested that the VPP and IPP are potential agents that can improve the endothelial dysfunction caused by EVs from Ang II-induced VSMCs.