Sex-Specific Effects of Resveratrol and Metformin on Endothelial Dysfunction

Endothelial dysfunction and mitochondrial impairment represent critical early drivers of atherogenesis, yet their progression often follows distinct patterns depending on biological sex. Understanding these mechanisms is essential for developing targeted therapeutic strategies in metabolic research and vascular biology contexts.

Researchers utilized human induced pluripotent stem cell-derived endothelial cells (iPSC-EC) generated from peripheral blood mononuclear cells of six male and six female donors. The cells were stimulated with TNF-alpha to induce a pro-atherogenic phenotype, followed by treatment with resveratrol or metformin. Mitochondrial reactive oxygen species production, mitochondrial content, endothelial permeability, mitochondrial respiration, inflammatory mediators, and lactate dehydrogenase release were quantified in a sex-stratified manner.

In this TNF-alpha-driven human iPSC-EC inflammatory dysfunction model, male iPSC-EC displayed stronger mitochondrial superoxide signals, inflammatory activation, and endothelial barrier disruption compared to female counterparts. Conversely, female iPSC-EC showed a trend toward impaired mitochondrial respiration and reduced IL-10 levels. Treatment with resveratrol and metformin trended toward reducing selected TNF-alpha associated endothelial injury markers across both sexes.

Resveratrol and metformin attenuated TNF-alpha-associated oxidative stress, cytokine secretion, permeability, and LDH release in the model. Male cells primarily benefited from decreased mitochondrial superoxide signals and reduced inflammation, while female cells showed non-significant tendencies toward improved mitochondrial respiration and restoration of IL-10 levels. These findings highlight cellular sex as a critical determinant of endothelial immunometabolic responses to inflammatory stress.

These results suggest that resveratrol- and metformin-based strategies for vascular protection should be evaluated in a sex-aware manner. The study underscores the importance of considering biological sex when investigating cardiometabolic modulators in human cell models, as male and female cells exhibit distinct vulnerabilities and response profiles to oxidative stress and inflammatory stimuli.