Little is known about these three production pathways in the human vasculature or in the neonatal period. Neonatal CBS deficiency manifests as homocystinuria associated with neurodevelopmental delay and skeletal and vascular abnormalities, highlighting the importance of this pathway not only in the brain, but in a number of other systems, including the vasculature. Clearly future studies will need to address all enzymes in the H2S production pathway. Tanshinone-I Further elucidation of the activity of these enzymes will help to define possible intervention strategies. A limitation of our study is that whilst we have demonstrated a clear correlation between outcome, microvascular blood flow and H2S production, this does not prove causation. Nevertheless we believe that our study provides strong clinical data that this pathway is Kalopanaxsaponin-H involved in microvascular tone regulation during circulatory transition. Furthermore, it highlights both the need for mechanistic studies utilising available animal models, and alternative measures of H2S production. Exhaled H2S may provide us with better temporal resolution of H2S production. These results provide the first evidence that H2S may play a role in maintaining microvascular tone of the neonate in the perinatal period. Thiosulphate levels were found to be highest in those neonates at greatest risk of microvascular dysfunction characterized by inappropriate peripheral vasodilatation �C very preterm male neonates born at 28 weeks completed gestation or less, suggesting that overproduction of H2S may contribute to microvascular dysfunction in neonates and thus to both their mortality and long term morbidity. The hydrogen sulphide pathway potentially represents a novel therapeutic target for the selective control of vascular tone and development during fetal-to-neonatal circulatory transition, which may help to reduce cardiovascular compromise following preterm birth, leading to better short- and long- term outcomes for this vulnerable group. cardiovascular compromise following preterm birth, leading to better short- and long- term outcomes for this vulnerable group.