Abstract
Significance: Hypertension has major health consequences, which is associated with endothelial dysfunction. Endothelial nitric oxide synthase (eNOS)-produced nitric oxide (NO) signaling in the vasculature plays an important role in maintaining vascular homeostasis. Considering the importance of NO system, this review aims to provide a brief overview of the biochemistry of members of NO signaling, including GTPCH1 [guanosine 5'-triphosphate (GTP) cyclohydrolase 1], tetrahydrobiopterin (BH(4)), and eNOS. Recent Advances: Being NO signaling activators and regulators of eNOS signaling, BH(4) treatment is getting widespread attention either as potential therapeutic agents or as preventive agents. Recent clinical trials also support that BH(4) treatment could be considered a promising therapeutic in hypertension. Critical Issues: Under conditions of BH(4) depletion, eNOS-generated superoxides trigger pathological events. Abnormalities in NO availability and BH(4) deficiency lead to disturbed redox regulation causing pathological events. This disturbed signaling influences the development of systemic hypertension as well as pulmonary hypertension. Future Directions: Considering the importance of BH(4) and NO to improve the translational significance, it is essential to continue research on this field to manipulate BH(4) to increase the efficacy for treating hypertension. Thus, this review also examines the current state of knowledge on the effects of eNOS activators on preclinical models and humans to utilize this information for potential therapy.