The fetal cerebral circulation: three decades of exploration by the LLU Center for Perinatal Biology.

For more than three decades, research programs in the Center of Perinatal Biology have focused on the vascular biology of the fetal cerebral circulation. In the 1980s, research in the Center demonstrated that cerebral autoregulation operated over a narrower pressure range, and was more vulnerable to insults, in fetuses than in adults. Other studies were among the first to establish that compared to adult cerebral arteries, fetal cerebral arteries were more hydrated, contained smaller smooth muscle cells and less connective tissue, and had endothelium less capable of producing NO. Work in the 1990s revealed that pregnancy depressed reactivity to NO in extra-cerebral arteries, but elevated it in cerebral arteries through effects involving changes in cGMP metabolism. Comparative studies verified that fetal lamb cerebral arteries were an excellent model for cerebral arteries from human infants. Biochemical studies demonstrated that cGMP metabolism was dramatically upregulated, but that contraction was far more dependent on calcium influx, in fetal compared to adult cerebral arteries. Further studies established that chronic hypoxia accelerates functional maturation of fetal cerebral arteries, as indicated by increased contractile responses to adrenergic agonists and perivascular adrenergic nerves. In the 2000s, studies of signal transduction established age-dependent roles for PKG, PKC, PKA, ERK, ODC, IP3, myofilament calcium sensitivity, and many other mechanisms. These diverse studies clearly demonstrated that fetal cerebral arteries were functionally quite distinct compared to adult cerebral arteries. In the current decade, research in the Center has expanded to a more molecular focus on epigenetic mechanisms and their role in fetal vascular adaptation to chronic hypoxia, maternal drug abuse, and nutrient deprivation. Overall, the past three decades have transformed thinking about, and understanding of, the fetal cerebral circulation due in no small part to the sustained research efforts by faculty and staff in the Center for Perinatal Biology.