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

## TL;DR

Preeclampsia is a vascular disorder caused by two key factors involving the VEGF-HO-1-CSE axis, offering new insights for diagnosis and treatment.

## Contribution

The paper introduces the concept of preeclampsia as a 'double-hit' vascular disorder and proposes a framework for risk stratification and treatment based on the VEGF-HO-1-CSE axis.

## Key findings

- Excess placental sFlt-1 neutralizes VEGF and PlGF, leading to endothelial dysfunction and hypertension.
- HO-1 and CSE/H2S pathways act as protective mechanisms against anti-angiogenic factors and oxidative stress.
- The H2S-donor prodrug MZe786 improves maternal and fetal outcomes in preclinical models of preeclampsia.

## 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, the failure of endogenous vascular brakes, heme oxygenase-1 (HO-1/CO) and cystathionine-γ-lyase (CSE)/hydrogen sulfide (H2S) removes physiological restraint on anti-angiogenic factor release (sFlt-1; soluble endoglin) and amplifies 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 orally administered H2S-donor prodrug MZe786 restores the HO-1/CSE axis, lowers sFlt-1 and soluble endoglin (sEng), and improves maternal haemodynamics and foetal outcomes across complementary pregnancy models, and we outline the role of sFlt-1/PlGF and M-PREG-based triage in clinical decision making. While valuable for short-term triage, current sFlt-1/PlGF-based approaches 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 informed by the double hit framework, and prevention strategies, pairing early risk stratification with mechanism-informed interventions.