Perinatal depression impairs placental angiogenesis and fetal growth in mice: protective effects of betaine supplementation

Introduction: Perinatal depression (PND) is the most common psychiatric disorder experienced during pregnancy and postpartum and is characterized by persistent low mood, difficulty adapting to gestational changes, helplessness, social withdrawal, and, in severe cases, suicidal or infanticidal thoughts. In this study, using a mouse model of PND, we examined the impact of PND on placental angioneurotrophic signaling, namely vascular endothelial growth factor (VEGF), VEGF receptor-1 (VEGFR1), and brain-derived neurotrophic factor (BDNF), and determined whether placental hypoxia precipitates impaired angiogenesis and fetal growth restrictions (FGR). Additionally, we evaluated the therapeutic potential of betaine in restoring placental function and fetal growth. Methods: To establish a PND model, pregnant C57BL/6 mice (n = 40) underwent 6 weeks of pre-mating chronic unpredictable mild stress (CUMS) combined with social isolation, continued until gestational day (GD) 14; non-stressed littermates served as controls (n = 10). Model dams were randomized to receive physiological saline vehicle (10 mL/kg/day, DD, n = 10), low-dose betaine (50 mg/kg/day, DD+LB, n = 10), high-dose betaine (200 mg/kg/day, DD+HB, n = 10), or escitalopram (10 mg/kg/day, DD+ESC, n = 10). Stress and treatments continued until gestational day (GD) 17. On GD 18, fetal and placental weights were recorded and placental efficiency calculated. Placental levels of VEGF, VEGFR1, BDNF, and hypoxia-inducible factor-1α (HIF-1α) were quantified using reverse transcription quantitative polymerase chain reaction and western blot. Microvascular density (MVD) and vascular architecture were assessed using CD34 immunohistochemistry and hematoxylin-eosin staining. Results: CUMS with social isolation evoked robust depression- and anxiety-like behaviors and attenuated maternal weight gain, thereby validating the PND model. PND resulted in significant fetal growth restriction, decreased placental efficiency, and marked reductions in placental BDNF and VEGF. These alterations coincided with elevated HIF-1α, indicating placental hypoxia. High-dose betaine reversed these deficits, restoring fetal weight and placental efficiency to control levels while upregulating placental BDNF and VEGF expression. Histologically, high-dose betaine increased MVD and improved vascular perfusion. Conclusions: These findings highlight betaine as a promising, low-risk intervention for preventing PND-associated fetal complications.