Preeclampsia Is a Double-Hit Vascular Disorder: The VEGF-HO-1-CSE Axis

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Abstract
Preeclampsia is a double-hit vascular disorder centred on the VEGF-HO-1-CSE axis. First, excess placental soluble Flt-1 (sFlt-1) neutralises vascular endothelial growth factor (VEGF) and placental growth factor (PlGF), producing an angiogenic deficit that drives endothelial dysfunction, hypertension, proteinuria and end-organ injury. Second, failure of endogenous vascular brakes, heme oxygenase-1 (HO-1/CO) and cystathionine-γ-lyase (CSE)/hydrogen sulfide (H2S), amplifies anti-angiogenic factor release (sFlt-1, soluble endoglin) and oxidative-inflammatory stress, lowering the threshold at which VEGF loss precipitates severe disease. We synthesise human, animal and translational data that (i) establish placental sFlt-1 source and release, (ii) demonstrate human mechanistic causality via sFlt-1 removal, (iii) show prospective clinical validation that sFlt-1 rises and free PlGF falls before disease onset, and (iv) identify HO-1 and CSE/H2S as protective pathways that restrain anti-angiogenic drive. Finally, we summarise preclinical evidence that the oral H2S-donor MZe786 restores the HO-1/CSE axis, lowers sFlt-1, improves maternal haemodynamics and fetal outcomes across complementary pregnancy models, and outline the role of sFlt-1/PlGF-based triage (PROGNOSIS) in clinical decision-making. This reactive tool, while valuable, cannot sub-stratify among positive cases. Framing severe preeclampsia as a double-hit vascular disorder provides a biologically grounded framework that can inform risk stratification strategies like M-PREG®, a clinical decision support system, and prevention strategies, pairing early risk stratification with mechanism-informed interventions.

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