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

Area of Science:

• Obstetrics and Gynecology
• Vascular Biology
• Maternal-Fetal Medicine

Background:

• Preeclampsia is a severe pregnancy complication characterized by a "double-hit" vascular disorder.
• The disorder involves an imbalance in angiogenic factors, specifically excess soluble Flt-1 (sFlt-1), and impaired endogenous protective pathways like heme oxygenase-1 (HO-1) and cystathionine-γ-lyase (CSE).
• This imbalance leads to endothelial dysfunction, hypertension, and end-organ damage.

Purpose of the Study:

• To synthesize evidence establishing the role of placental sFlt-1 in preeclampsia pathogenesis.
• To validate HO-1 and CSE/H2S as critical protective pathways that restrain anti-angiogenic drive.
• To evaluate the therapeutic potential of an H2S-donor prodrug (MZe786) in preclinical models of preeclampsia.

Main Methods:

• Review and synthesis of human, animal, and translational data.
• Analysis of sFlt-1 source and release mechanisms.
• Assessment of mechanistic causality through sFlt-1 removal in human studies.
• Prospective clinical validation of sFlt-1 and free PlGF as predictive biomarkers.
• Preclinical evaluation of MZe786's efficacy in restoring HO-1/CSE axis and improving maternal-fetal outcomes.

Main Results:

• Placental sFlt-1 is a key driver of the angiogenic deficit in preeclampsia.
• Reduced activity of HO-1/CO and CSE/H2S pathways exacerbates oxidative stress and disease severity.
• Elevated sFlt-1 and decreased free PlGF precede disease onset, offering predictive value.
• Preclinical studies demonstrate MZe786 restores HO-1/CSE function, reduces anti-angiogenic factors, and improves hemodynamic and fetal parameters.
• The "double-hit" framework provides a basis for risk stratification and mechanism-informed interventions.

Conclusions:

• Preeclampsia is fundamentally a double-hit vascular disorder driven by sFlt-1 and impaired HO-1/CSE pathways.
• Targeting the HO-1/CSE axis with agents like MZe786 represents a promising therapeutic strategy.
• The "double-hit" framework and biomarkers like sFlt-1/PlGF aid in risk stratification and clinical decision-making for preeclampsia.