Polyamine-Based Therapeutic Strategy for Hypertensive Pregnancy: Spermidine Reverses Placental Vascular and Endothelial Dysfunction in Preeclampsia

Objective: Our preliminary research identifies altered polyamine metabolism, particularly, spermidine levels, as a novel contributor to placental pathology in preeclampsia. We aim to translate these findings by clinically validating its association with the disease, characterizing the underlying molecular mechanisms, and evaluating its therapeutic potential as a novel strategy. Design and method: Urinary spermidine concentrations were quantified using LC-MS/MS metabolomics in a cohort of preeclamptic (n=25) and normotensive pregnancies (n=25). HTR-8/ SVneo trophoblasts were supplemented with spermidine (100uM) under hypoxic (1% Oxygen) conditions to model the preeclamptic placenta. Network pharmacology and western blotting were employed to identify core molecular pathways and targets. In vivo, L - NAME (250 mg/kg/day) rat model of preeclampsia was treated with spermidine (10 mg/kg/day) supplementation and compared against standard low-dose aspirin (1.5 mg/kg/day). Maternal cardiac function was assessed by echocardiography using animal imaging system. Placental oxygenation was measured using photoacoustic imaging and the comprehensive assessment of placental, and fetal phenotypes, was performed. Results: Spermidine levels were significantly lower in preeclamptic patients, with a 2.5 fold decrease compared to controls. In vitro, spermidine supplementation restored trophoblast functionality under hypoxic conditions, enhancing proliferation, migration, and invasion capabilities. Mechanistic analyses identified the PI3K-Akt/HIF-1a signalling axis as the central pathway mediating vascular protection. In vivo, spermidine reduced maternal blood pressure (22% decrease) and proteinuria (50% decrease), with a 67% improvement in placental oxygenation. These changes translated to increased placental and fetal weights. Further, echocardiography revealed improved left ventricular mass (SMD:93.30, P=0.007 at GD 18), cardiac output (SMD:-12.37, P=0.03 at GD 14), and stroke volume (SMD:-36.44, P=0.004 at GD 14) restoring cardiac parameters toward control levels. Spermidine also improved endothelial function by rebalancing key placental angiogenic (VEGF, PlGF) and vasoactive (endothelin-1, nitric oxide) markers. Conclusions: Spermidine supplementation significantly alleviates preeclampsia symptoms by restoring placental function and improving deteriorated cardiac function. These results provide robust mechanistic and therapeutic evidence for treatment of preeclampsia. However, the findings strongly advocate further clinical validation of spermidine as a novel therapeutic agent.