Emerging evidences indicate that a microbial imbalance (dysbiosis) is linked to several diseases including metabolic cardiovascular diseases. A fecal microbiota transplantation from hypertensive human donor to germ-free mice causes blood pressure elevation, suggesting that gut microbiome may mediate development of hypertension. One recent report demonstrated that an increasing number of gram-positive Streptococcus was found in the feces of adult spontaneously hypertensive rats (SHR) with an increased intestinal permeability (Santisteban et al., 2017). However, detailed mechanism by which the dysbiosis induces an increased blood pressure remains unknown. We recently found an elevated plasma level of streptolysin O (SLO), a streptococcal exotoxin, in younger SHR aged 10-14 week-old. Treatment of vascular tissues with SLO in vitro impaired endothelial-dependent vasorelaxation, which was mediated by PKCβ-induced phosphorylation of an inhibitory site of endothelial nitric oxide synthase, possibly through TLR4. Intravenous administration of SLO in normal rats impaired an acetylcholine-induced decrease in blood pressure. We confirmed that intestinal permeability was increased with a decreased tight junction protein in younger SHR (10-14-week-old). We conclude that streptococcal exotoxin causes vascular endothelial dysfunction and may contribute to a dysregulation of blood pressure control. This finding might contribute to further understanding of the potential roles of circulating enteric toxin in the pathogenesis of hypertension.