{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T00:58:51Z","timestamp":1792803531623,"version":"4.5.0"},"reference-count":71,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T00:00:00Z","timestamp":1773360000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006041","name":"Innovate UK","doi-asserted-by":"publisher","award":["10066967"],"award-info":[{"award-number":["10066967"]}],"id":[{"id":"10.13039\/501100006041","id-type":"DOI","asserted-by":"publisher"}]},{"name":"MirZyme Therapeutics Limited","id":[{"id":"https:\/\/ror.org\/00ps4k811","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>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-\u03b3-lyase (CSE)\/hydrogen sulfide (H2S) removes physiological restraint on anti-angiogenic factor release (sFlt-1; soluble endoglin) and amplifies oxidative\u2013inflammatory 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\u00ae, a clinical decision support system informed by the double hit framework, and prevention strategies, pairing early risk stratification with mechanism-informed interventions.<\/jats:p>","DOI":"10.3390\/biom16030436","type":"journal-article","created":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T11:12:25Z","timestamp":1773400345000},"page":"436","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Preeclampsia Is a Double-Hit Vascular Disorder: The VEGF-HO-1-CSE Axis"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8755-8546","authenticated-orcid":false,"given":"Asif","family":"Ahmed","sequence":"first","affiliation":[{"name":"Mirzyme Therapeutics Limited, Innovation Birmingham Campus, Faraday Wharf, Holt Street, Birmingham B7 4BB, UK"},{"name":"Faculty of Environmental and Life Sciences, School of Health Sciences, President\u2019s Office, University of Southampton, Southampton SO17 1BJ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen K.","family":"Smith","sequence":"additional","affiliation":[{"name":"Mirzyme Therapeutics Limited, Innovation Birmingham Campus, Faraday Wharf, Holt Street, Birmingham B7 4BB, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9294-0475","authenticated-orcid":false,"given":"Shakil","family":"Ahmad","sequence":"additional","affiliation":[{"name":"Aston Medical Research Institute, Aston Medical School, Aston University, Birmingham B4 7ET, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keqing","family":"Wang","sequence":"additional","affiliation":[{"name":"Aston Medical Research Institute, Aston Medical School, Aston University, Birmingham B4 7ET, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1673","DOI":"10.2105\/AJPH.2021.306375","article-title":"Racial and Ethnic Disparities in Maternal Mortality in the United States Using Enhanced Vital Records, 2016\u20132017","volume":"111","author":"MacDorman","year":"2021","journal-title":"Am. 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