Maternal Diabetes Mellitus (DM) predisposes the infant (IDM) to thrombosis. In the adult with DM, abnormal metabolism of arachidonic acid (AA) by the platelet and vessel occurs leading to increased proaggregatoy platelet Thromboxane A2, and decreased antiaggregatory vascular PGI2. This imbalance in AA metabolism plays a role in diabetic angiopathy. Other complications in the IDM include RDS and congenital malformations. TXA2 is a potent pulmonary vasoconstrictor, and induces growth retardation and anomalies in chick embryos. Thus, changes in prostaglandin metabolites may play an important role in other complications seen in the IDM besides thromboses. Evidence from our group suggests that abnormal platelet and vascular AA metabolism occurs in the IDM. We plan to evaluate platelet phospholipid and AA metabolism during the diabetic pregnancy, at delivery, in cord blood, and in the IDM. This will enable us to identify whether changes occur in prostaglandin dependent and independent (diglyceride, PA and lyso-PA) pathways. AA release, conversion to cyclo-oxygenase and lipoxygenase metabolites will be quantitated. If our preliminary evidence that increased AA release occurs in platelets from diabetics is confirmed, attempts to modify this abnormality with drugs in vitro will be pursued. Studies on vascular AA metabolism will include identification of the cause(s) for the decrease in 6KPGF1Alpha in IDM vasculature and complete characterization of the HETES that are elevated in the IDM. Effects of these HETES on angiogenesis will be evaluated using endothelial migration and proliferation assays. Levels of free and bound plasma TXB2, 6KPGF1Alpha and HETES during pregnancy, at delivery, and in neonate will be performed with follow up to evaluate whether abnormalities persist. An evaluation of protein bound prostanoids and correlations between PGI2 and TXA2 half-lives, prostanoid binding proteins and protein glycosylation will be assessed. Platelet endothelial cell interactions will be studied in vitro using control and diabetic platelets and control and IDM vasculature. Identification of consistent maternal abnormalities that could predict neonatal status, and AA metabolism in reference to glucose homeostasis will be assessed. Changes in neonatal AA metabolic parameters and neonatal evidence of thromboses, RDS, pulmonary hypertension, growth anomalies, and malformations will be evaluated. The investigations outlined should provide further insights into phospholipid and AA metabolism in diabetes. The in vitro drug studies could provide us with a preliminary approach to therapeutic intervention.
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