Work

Hydroxytyrosol attenuates intimal hyperplasia in in vitro and ex vivo human saphenous vein models: association with Akt and Nrf2/HO-1 signalling

Year: 2026

Type: article

Abstract: Background : Venous intimal hyperplasia (VIH) contributes to luminal vascular thickening, which compromises the long-term patency of coronary artery bypass grafting (CABG) grafts and negatively impacts the outcomes of percutaneous coronary intervention. Antiproliferative drugs that impair endothelial cell (EC) function can exacerbate VIH. Additionally, endothelial dysfunction leads to an imbalance in reactive oxygen species, further inducing excessive vascular remodelling. Hydroxytyrosol (HT), an olive oil derivative, has been proved to exert antioxidant, anti-inflammatory, and antiproliferative effects. We hypothesize that HT could inhibit smooth muscle cell (SMC) proliferation without compromising EC homeostasis, thus emerging as an adjuvant solution to prevent intimal hyperplasia in patients undergoing CABG. Methods & Results : Dose-response experiments of HT were conducted in vitro on ECs and PDGF-BB-stimulated SMCs. In vitro , HT at concentrations ranging from 40 μM to 320 μM, significantly inhibited PDGF-induced SMC proliferation, migration, and chemotaxis via downregulating Akt pathway. In contrast, HT concentrations below 50 μM preserved EC viability, proliferation, and migration. Additionally, HT activated the Nrf2/HO-1 antioxidant pathway in both cell types. Therefore, HT at 50uM was then tested in an ex vivo human saphenous vein (hSV) ring culture. In the ex vivo hSV model, a significant increase in cellular proliferation was observed from day 0 to day 21. HT treatment reduced intimal thickness by 44% and SMC proliferation by 53% (p=0.004), likely due to the inhibition of Akt and vimentin, along with the HO-1 activation. Conclusions : Our findings underscore the therapeutic potential of HT in preventing intimal hyperplasia as per its balanced effects on regulating the biological function of vessel resident cells. Further research is warranted to evaluate HT’s effect on reendothelialization, particularly using 3D disease models or animal studies.

Source: Frontiers in Pharmacology

DOI: 10.3389/fphar.2026.1962884