Project 462691

Before birth, blood flow to fetal lungs is minimal and oxygen (O2) is provided by the placenta. The ductus arteriosus (DA), an artery connecting the pulmonary artery (PA) and aorta, allows blood from the right heart to bypass the unventilated lungs. With the first breath, O2 rises, simultaneously causing DA constriction, which diverts blood to the lungs, and pulmonary artery (PA) relaxation which accommodates increased blood flow and gas exchange. The mechanism for the opposing O2-responses of fetal PA and DA remains one of the great, unresolved mysteries of human physiology. This mystery has practical implications since failure of O2-sensing contributes to two congenital heart diseases, especially in premature infants: persistent ductus arteriosus and persistent pulmonary hypertension of the newborn. We have established that: 1) core mechanisms of O2-induced DA constriction and PA dilation, reside in the smooth muscle cells (SMC). Here the mitochondrial electron transport chain (ETC) serves as an O2-sensor, varying production of reactive oxygen species (ROS) in proportion to O2. ROS act as signaling molecules and regulate vascular tone by controlling the activity of ion channels and kinases. 2) In adult PAs we identified NDUFS2, an Fe/S center within ETC Complex I, as an O2-sensor. 3) In adult arteries with opposing O2-responses we discovered spatial heterogeneity in the composition and function of mitochondrial ETC Complexes I and III. However, in fetal DA and PA neither the identity of the mitochondrial O2-sensor, nor the relevance of spatial mitochondrial heterogeneity is known. Using term and preterm rabbits and term human DASMC we investigate the identity of the fetal O2-sensor and evaluate whether spatial heterogeneity in mitochondrial structure and function between the DA and PA underlies their opposing O2-responses. Impact: We will define the mechanism for the opposing response of DA vs PA to O2 and identify new treatments for congenital heart diseases.