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

Background Venous intimal hyperplasia remains a major cause of saphenous vein graft failure following coronary artery bypass grafting Current antiproliferative strategies often impair endothelial cell function, exacerbating vascular injury. Hydroxytyrosol (HT), a bioactive olive phenolic compound, exhibits antioxidant and anti-inflammatory properties, but its coordinated effects on vascular smooth muscle cells and ECs remain unclear. Methods Primary human saphenous vein-derived SMCs and ECs were exposed to graded concentrations of HT to evaluate cell viability, proliferation, migration, chemotaxis, and signalling responses. A human saphenous vein ring (hSVR) culture model was used to investigate the effects of HT on spontaneous ex vivo intimal hyperplasia. Results HT (20–320 μM) significantly inhibited PDGF-BB-induced SMC proliferation, migration, and chemotaxis accompanied by reduced Akt signalling. In contrast, HT at concentrations ≤50 μM did not produce a statistically significant reduction in EC viability, proliferation, and migration while activating the Nrf2/HO-1 antioxidant pathway. In the ex vivo hSVR model, 50 μM HT reduced intimal thickness by 45.2% and significantly attenuated neointimal cell proliferation at day 21. HT also suppressed Akt activation, enhanced HO-1 expression, and reduced vimentin expression, consistent with attenuation of vascular remodeling. Attempts to evaluate re-endothelialization were inconclusive because seeded ECs failed to establish continuous luminal coverage in the ex vivo model. Conclusion Hydroxytyrosol selectively inhibits SMC activation while preserving endothelial homeostasis associated with differential modulation of the Akt and Nrf2/HO-1 pathways. These findings demonstrate that HT effectively attenuates intimal hyperplasia in a human ex vivo vein model and support its potential as an adjunctive strategy for improving vein graft patency. Further studies using perfused vascular systems or in vivo models are required to determine its effects on endothelial repair and re-endothelialisation.