Folic acid drives metabolic reprogramming to alleviate Toxoplasma gondii antigen-induced vascular injury

Infection with parasites is usually accompanied by vascular problems. To investigate the detrimental effects of parasites on blood vessels. We used Toxoplasma gondii (T. gondii), a prevalent intracellular parasite with the potential to induce vascular damage, as an example. In addition to a murine model, a novel human pluripotent stem cell-derived blood vessel organoid (VO) model was emoployed to examined the effect of T. gondii antigens on vessels. We found that T. gondii antigen-induced vascular injury is correlated with inflammation, cellular apoptosis, degradation of extracellular matrix, and disruption of cellular tight junctions. T. gondii antigens also promotes the phenotypic transition of smooth muscle cells (SMCs) from contraction phenotype to secretion phenotype. Interestingly, we found that prophylactic addition of folic acid (FA) appears to counteract all such effects, partially restoring vascular homeostasis. Previous studies on the protective effects of FA on blood vessels remains in its infancy. To reveal the mechanism of FA-mediated vasoprotective effects, we performed transcriptomic and metabolomic analyses. The results show that T. gondii antigen disrupts several vital metabolic pathways crucial for vessel function. Significantly, FA alleviates these metabolic disorders. The protective effect of FA is associated with vascular metabolic reprogramming. This study not only elucidates the mechanisms underlying T. gondii antigen-induced vascular injury, but also reveals a metabolic regulatory role of FA in vascular repair, which has potential value in clinical applications. Additionally, VOs derived from human stem cells are amenable systems for modelling and identifying the regulators and drugs of vascular injury.