Abstract 128: Disruption of Methylarginine Metabolism Impairs Vascular Homeostasis During Pregnancy

Abstract

Endogenously produced asymmetrically methylated forms of L-arginine (ADMA) competitively inhibit all three isoforms of nitric oxide synthase enzymes and therefore have the potential to exert significant cardiovascular effects. Elevated circulating ADMA concentrations have been reported in a number of cardiovascular disease states, including preeclampsia, suggesting that impaired ADMA metabolism may contribute to pathology. In order to test the causal relationship between ADMA concentrations and hemodynamics in pregnancy we employed radiotelemetric measurement of hemodynamic function in mice with either global or fetal-specific deletion of the predominant ADMA metabolising enzyme dimethylarginine dimethylaminohydrolase 1 (DDAH1). Global deletion of DDAH1 in non-pregnant female mice caused an elevation in circulating ADMA concentrations (2.851±0.289 vs 1.216±0.072 μM p<0.01) and blood pressure (118±2.28 vs 110.36±0.82 mmHg p<0.05). During the first and second trimesters of pregnancy DDAH1 -/- mice showed no further elevation in ADMA and normal pregnancy related changes in blood pressure were observed. However, during the third trimester ADMA levels in DDAH1 -/- mice increased further and this was associated with increased concentrations of sEng and sFlt1 (2288±301.58 vs 1181.35 ± 161.83 pg/ml p<0.01 and 153.31 ± 8.57 vs 114.42 ± 8.79 ng/ml p<0.001) and an exaggerated hypertensive response (115.773 ± 3.7 vs 101.93 ± 3.27 mmHg p<0.05). Fetal-specific deletion of DDAH1 elevated fetal ADMA concentrations (4.97 ± 0.29 μM vs 1.7 ± 0.12 μM p<0.001) but did not impact on maternal ADMA concentrations or blood pressure during early pregnancy. However in the third trimester a significant elevation in maternal ADMA concentrations was detected (2.49 ± 0.17 vs 1.75 ± 0.13 μM p<0.01) and was associated with an elevation in maternal blood pressure. No changes in sEng or sFLt1 were detectable in fetal-specific DDAH1 -/- mice. Our data indicate that elevated ADMA is sufficient to increase levels of sFLlt1 and sEng and disrupt maternal hemodynamics. The fetus is a significant source of ADMA in late pregnancy suggesting that dysfunctional fetal ADMA metabolism is sufficient to impair maternal hemodynamic function.