{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T15:23:01Z","timestamp":1784301781830,"version":"3.55.0"},"reference-count":53,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2025,8,8]],"date-time":"2025-08-08T00:00:00Z","timestamp":1754611200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health","award":["1R15 HD108743-01"],"award-info":[{"award-number":["1R15 HD108743-01"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Preeclampsia (PE) is a leading cause of maternal and fetal morbidity that affects 2\u20138% of pregnancies worldwide, driven by placental dysfunction and systemic inflammation. Growth arrest-specific protein 6 (Gas6) and its receptor AXL play pivotal roles in PE pathogenesis, promoting trophoblast impairment and vascular dysregulation. This study investigated the transcriptomic reversal effects of AXL Receptor Tyrosine Kinase (AXL) inhibition in a Gas6-induced rat model of PE using RNA sequencing (RNA-seq). Pregnant rats were administered Gas6 to induce PE-like symptoms such as hypertension and proteinuria; a subset also received the AXL inhibitor R428. RNA-seq of placental tissues revealed 2331 differentially expressed genes (DEGs) in Gas6-AXLi versus Gas6 (1277 upregulated, 1054 downregulated). Protein\u2013protein interaction networks and Gene Ontology enrichment highlighted upregulated mitochondrial functions, including electron transport chain components (e.g., NDUFC2, COX5A), suggesting enhanced energy metabolism. In the secondary analysis that compared Gas6 to Control, Gas6-upregulated extracellular matrix proteins (e.g., COL4A1, LAMC1) linked to fibrosis were reversed by AXL inhibition, indicating ameliorated placental remodeling. AXL inhibition activated compensatory pathways beyond Gas6 blockade, unveiling novel mechanisms for PE resolution. These findings position AXL inhibitors as promising therapeutics, offering insights into mitochondrial and fibrotic targets to mitigate this enigmatic disorder.<\/jats:p>","DOI":"10.3390\/cells14161229","type":"journal-article","created":{"date-parts":[[2025,8,8]],"date-time":"2025-08-08T13:20:09Z","timestamp":1754659209000},"page":"1229","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Reversing Preeclampsia Pathology: AXL Inhibition Restores Mitochondrial Function and ECM Balance"],"prefix":"10.3390","volume":"14","author":[{"given":"Archarlie","family":"Chou","sequence":"first","affiliation":[{"name":"Department of Microbiology and Molecular Biology, Brigham Young University, Provo, UT 84602, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Davidson","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Physiology, Brigham Young University, Provo, UT 84602, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0931-3025","authenticated-orcid":false,"given":"Paul R.","family":"Reynolds","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Physiology, Brigham Young University, Provo, UT 84602, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7930-8160","authenticated-orcid":false,"given":"Brett E.","family":"Pickett","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Biology, Brigham Young University, Provo, UT 84602, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8818-8786","authenticated-orcid":false,"given":"Juan A.","family":"Arroyo","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Physiology, Brigham Young University, Provo, UT 84602, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e323","DOI":"10.1016\/S2214-109X(14)70227-X","article-title":"Global causes of maternal death: A WHO systematic analysis","volume":"2","author":"Say","year":"2014","journal-title":"Lancet Glob. 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