Abstract
Elevated plasma homocysteine levels are considered as a risk factor for cardiovascular diseases as well as preeclampsia—a pregnancy disorder characterized by hypertension and proteinuria. We previously generated mice lacking cystathionine γ-lyase (Cth) as cystathioninuria models and found them to be with cystathioninemia/homocysteinemia. We investigated whether Cth-deficient (Cth−/−) pregnant mice display any features of preeclampsia. Cth−/− females developed normally but showed mild hypertension (~10 mmHg systolic blood pressure elevation) in late pregnancy and mild proteinuria throughout development/pregnancy. Cth−/− dams had normal numbers of pups and exhibited normal maternal behavior except slightly lower breastfeeding activity. However, half of them could not raise their pups owing to defective lactation; they could produce/store the first milk in their mammary glands but not often provide milk to their pups after the first ejection. The serum oxytocin levels and oxytocin receptor expression in the mammary glands were comparable between wild-type and Cth−/− dams, but the contraction responses of mammary gland myoepithelial cells to oxytocin were significantly lower in Cth−/− dams. The contraction responses to oxytocin were lower in uteruses isolated from Cth−/− mice. Our results suggest that elevated homocysteine or other unknown factors in preeclampsia-like Cth−/− dams interfere with oxytocin that regulates milk ejection reflex.
Highlights
Elevated plasma levels of homocysteine, a sulfur-containing amino acid intermediate in methionine metabolism, are widely known as an independent risk factor for cardiovascular diseases (CVDs) such as myocardial infarction, stroke, and venous thromboembolism [1,2,3,4,5,6]
We report preeclampsia-like hypertension/proteinuria during late pregnancy as well as partial lactation failure due to impaired oxytocin responses in cystathionine γ-lyase (Cth)−/− mice
Our Cth−/− dams showed hypertension during pregnancy and mild proteinuria during development/pregnancy (Figures 1 and 2), which are the typical features of pregnancy hypertension syndrome/preeclampsia [48], but we could not clarify whether these preeclampsia-like phenotypes were induced by homocysteinemia
Summary
Elevated plasma levels of homocysteine, a sulfur-containing amino acid intermediate in methionine metabolism, are widely known as an independent risk factor for cardiovascular diseases (CVDs) such as myocardial infarction, stroke, and venous thromboembolism [1,2,3,4,5,6]. Folic acid food/supplement fortification is underway in many countries to lower plasma homocysteine levels (by activating remethylation of homocysteine to methionine) and thereby prevent the onset/progression of CVDs, pregnancy complications, and NTDs [12]. Patients with CBS-deficient “classical” homocystinuria show a variety of clinical symptoms including atherothrombosis, mental retardation, osteoporosis, lens dislocation, and Marfan-like skeletal abnormality [6]. For these reasons, homocystinuria is listed among the newborn screening tests in most developed countries [17]. Cbs-deficient mice have been generated as an animal model of homocystinuria, and they showed homocysteinemia/methioninemia and hepatic steatosis; severe juvenile deaths with unknown reasons (not NTDs) have been reported in these mice [18,19,20]. We first aimed to reveal whether homocysteinemic Cth−/− dams display any features of preeclampsia such as hypertension and proteinuria
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