Treatment with nebivolol results in the improvement of hypertension-induced endothelial cell (EC) dysfunction by reducing the factors that contribute to cellular senescence of the endothelium, a study has shown.
“The data indicate that this benefit is mainly associated with attenuation of TGF-β1-dependent senescence, reduction in inflammatory, and angiogenic signalling,” the investigators said.
Seventy-one patients with newly diagnosed hypertension were randomized to one of three groups based on the antihypertensive treatment: amlodipine, nebivolol, or perindopril. The investigators collected serum samples before and 6 weeks after treatment were applied to ECs in vitro to examine their angiogenic activity, cellular senescence, mitochondrial metabolism, and oxidative stress.
ECs exposed to serum from patients treated for 6 weeks showed significant changes in EC function, with varying effects across antihypertensive medications. [J Hypertens 2026;44:1780-1790]
Serum from patients treated with nebivolol yielded the most consistent benefits through decreases in EC proliferation and HIF-1α expression, potentially driven by lower levels of angiogenic factors including angiopoietin-1, basic fibroblast growth factor (bFGF), insulin-like growth factor 1 (IGF-1), and vascular endothelial growth factor (VEGF).
Furthermore, serum from nebivolol-treated patients contained lower levels of proinflammatory cytokine (ie, E-selectin, P-selectin, monocyte chemoattractant protein-1, and tumour necrosis factor α) and reduced TGF-β1, which are associated with EC senescence induced by hypertension.
Senescence biomarkers, including SA-β-Gal, 53BP1, and p16, decreased following nebivolol treatment. The reduction in SA-β-Gal was similar to that of TGF-β1 neutralizing antibodies. Moreover, a decrease in oxidative stress occurred, as shown by lower oxidized DNA product levels.
EC viability
“As we have previously shown, hypertension serum reduces the viability of ECs,” the investigators said. “This aligns with the widely accepted view that EC activity worsens as the disease progresses.” [Front Med (Lausanne) 2021;8:798958]
Such effect, however, is counterbalanced by increased proliferation, migration, and the ability to form tube-like structures, which preserve the integrity of the EC monolayer. [Mech Ageing Dev 2025;229:112128]
Antihypertensive medications had varying effects on these parameters since ECs show different responses to drugs with various mechanisms of action. [Int J Mol Sci 2019;20:3458]
For instance, serum from amlodipine-treated patients increased cell proliferation, whereas other processes remained unchanged. On the other hand, nebivolol use was associated with reduced proliferation and tubulogenesis, potentially reducing HIF-1α levels. Serum from patients treated with perindopril showed no significant effects. [Biomed Res Int 2015;2015:549412]
“This finding aligns with the existing, yet inconclusive, literature regarding the effects of perindopril. For instance, one study found that rabbits treated with perindopril exhibited enhanced endothelial regrowth after arterial injury compared with those receiving a placebo,” the investigators said. [Biomed Res Int 2015;2015:549412]
“Conversely, another study indicated that the active form of perindopril, perindoprilat, inhibited the formation of endothelial cell tubules, highlighting the antiangiogenic properties of this [drug],” they added. [Clin Cancer Res 2001;7:1073-1078]
“Indirect evidence of changes of mitochondrial parameters was observed; however, further studies are needed to elucidate the effects of nebivolol on mitochondrial function,” the investigators said. “These observations strengthen the rationale for considering pleiotropic endothelial effects when evaluating antihypertensive therapy.”