Abstract 1853 Pulmonary Vascular Biology Platform, Monday, 5/3

Factors regulating fetal pulmonary vascular tone and promoting the perinatal fall in pulmonary vascular resistance (PVR) are incompletely understood. In several adult circulations, estrogens can modulate expression of important vasoactive mediators and cause vasodilation. In addition, in previous studies of fetal lambs, we have found that prolonged infusions of exogenous estradiol increase pulmonary blood flow by nearly 3-fold. Nonetheless, the physiologic effects of endogenous estrogens in the fetal pulmonary circulation are unknown. We hypothesized that the progressive rise in estrogens in late gestation modulates fetal pulmonary vascular tone and augments the fall in PVR at birth. To address this hypothesis, we treated chronically instrumented fetal lambs with the specific estrogen receptor blocker ICI 182,780 and studied their responses to birth-related stimuli during cesarean section delivery studies. Surgery was performed on 9 fetal lambs at 128±2 days (term=147 days). Catheters were placed in the aorta, main pulmonary artery, and left atrium to measure pressure and in the left pulmonary artery (LPA) for selective drug infusions. An ultrasonic flow transducer was placed around the LPA to measure blood flow. After at least 72 hours recovery, baseline hemodynamic measurements were recorded. ICI 182,780 (5 µg/hr; ICI, n=5) or vehicle (0.5% DMSO, 1 cc/hr; CTRL, n=4) was then continuously infused into the LPA for 6 days. Baseline PVR was similar between groups and did not change in either group during the 6 day study period. At the end of the 6 day infusion, lambs were mechanically ventilated with hypoxic gas (to maintain fetal PaO2) and with 100% O2. ICI treatment completely blocked the fall in PVR in response to hypoxic ventilation (-35±4 vs. 14±8% change from baseline, CTRL vs. ICI, p<0.05). However, ventilation with 100% O2 caused a similar fall in PVR in both groups (-75±2 vs. -78±4% change from baseline, CTRL vs. ICI). We conclude that estrogen receptor blockade abolishes the fall in PVR induced by hypoxic ventilation in the fetal lamb. We speculate that prolonged exposure to endogenous estrogens in late gestation is a critical factor in preparing the lung circulation for birth and in facilitating the perinatal fall in PVR.