2. Academic Validation
  3. Venous Endothelial Cell Transcriptomic Profiling Implicates METAP1 in Preeclampsia

Venous Endothelial Cell Transcriptomic Profiling Implicates METAP1 in Preeclampsia

  • Circ Res. 2025 Jan 17;136(2):180-190. doi: 10.1161/CIRCRESAHA.124.324606.
Maria A Pabon 1,  Robert M Weisbrod 2,  Claire Castro 3,  Haobo Li 4,  Peng Xia 3,  Jiayi Kang 4,  Maddalena Ardissino 5 6 7 8,  Katherine E Economy 9,  Zihui Yang 3,  Yanxi Shi 3,  Eunice Kim 10,  Anna Perillo 11,  Leanne Barrett 11,  Jenifer M Brown 1 11,  Sanjay Divakaran 1 11,  Murat Cetinbas 12 13,  Ruslan I Sadreyev 12 13,  Antonio de Marvao 8 14 15,  Malissa J Wood 16,  Nandita S Scott 17,  Emily S Lau 3 17,  Jennifer E Ho 18,  Marcelo F Di Carli 1 11,  Jason D Roh 3 17,  Naomi M Hamburg 2,  Michael C Honigberg 3 17 19
Affiliations

Affiliations

  • 1 Cardiovascular Division (M.A.P., J.M.B., S.D., M.F.D.C.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
  • 2 Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA (R.M.W., N.M.H.).
  • 3 Cardiovascular Research Center (C.C., P.X., Z.Y., Y.S., E.S.L., J.D.R., M.C.H.), Massachusetts General Hospital, Boston, MA.
  • 4 Department of Anesthesia, Critical Care, and Pain Medicine (H.L., J.K.), Massachusetts General Hospital, Boston, MA.
  • 5 Department of Public Health and Primary Care, British Heart Foundation, Cardiovascular Epidemiology Unit (M.A.), University of Cambridge, United Kingdom.
  • 6 Victor Philip Dahdaleh National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics (M.A.), University of Cambridge, United Kingdom.
  • 7 National Heart and Lung Institute, Imperial College London, Hammersmith Hospital, United Kingdom (M.A.).
  • 8 Medical Research Council, Laboratory of Medical Sciences, Imperial College London, United Kingdom (M.A., A.d.M.).
  • 9 Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology (K.E.E.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
  • 10 Harvard University, Cambridge, MA (E.K.).
  • 11 Cardiovascular Imaging Program, Department of Medicine and Radiology (A.P., L.B., J.M.B., S.D., M.F.D.C.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
  • 12 Department of Molecular Biology (M.C., R.I.S.), Massachusetts General Hospital, Boston, MA.
  • 13 Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA (M.C., R.I.S.).
  • 14 Department of Women and Children's Health (A.d.M.), King's College London, United Kingdom.
  • 15 British Heart Foundation Centre of Research Excellence, School of Cardiovascular and Metabolic Medicine and Sciences (A.d.M.), King's College London, United Kingdom.
  • 16 Lee Health Heart Institute, Fort Myers, FL (M.J.W.).
  • 17 Cardiology Division (N.S.S., E.S.L., J.D.R., M.C.H.), Massachusetts General Hospital, Boston, MA.
  • 18 Cardiovascular Institute and Division of Cardiology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA (J.E.H.).
  • 19 Program in Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA (M.C.H.).
PMID: 39727051 DOI: 10.1161/CIRCRESAHA.124.324606
Abstract

Background: Preeclampsia is a hypertensive disorder of pregnancy characterized by systemic endothelial dysfunction. The pathophysiology of preeclampsia remains incompletely understood. This study used human venous endothelial cell (EC) transcriptional profiling to investigate potential novel mechanisms underlying EC dysfunction in preeclampsia.

Methods: Venous ECs were isolated from postpartum patients with severe preeclampsia and those with normotensive pregnancy using a J wire-based technique in the antecubital vein followed by CD144 (vascular endothelial Cadherin) magnetic bead isolation. Venous EC transcriptomes were compared between preeclamptic and normotensive individuals. Differentially expressed genes were carried forward for genetic validation using expression quantitative trait loci from the Genotype-Tissue Expression project as exposures for vascular-specific Mendelian randomization. Functional validation of the top candidate was performed in human umbilical vein ECs using gain- and loss-of-function genetic approaches.

Results: Seventeen individuals with preeclampsia and 7 normotensive controls were included. Pairwise analysis yielded 14 protein-coding genes nominally differentially expressed in participants with preeclampsia. Mendelian randomization revealed a significant association between higher genetically predicted METAP1 (methionyl Aminopeptidase 1) expression in aortic and tibial arterial tissues and greater risk of preeclampsia. METAP1 overexpression in human umbilical vein ECs decreased angiogenesis, with a 66% decrease in tube formation (P=7.9×10-3) and 72% decrease in cell proliferation (P=2.9×10-2). Furthermore, METAP1 overexpression decreased VEGFA expression and increased expression of multiple preeclampsia-related genes, for example, FLT1, INHBA, and IL1B. Conversely, METAP1 knockdown produced opposite effects on tube formation, cell proliferation, and inflammation-related gene expression.

Conclusions: In a cohort of early postpartum individuals, we observed greater METAP1 expression in venous ECs of women with preeclampsia versus normotensive delivery. Mendelian randomization supported a causal relationship between greater vascular METAP1 expression and higher preeclampsia risk, and functional experiments demonstrated antiangiogenic and proinflammatory effects of METAP1 in human ECs consistent with alterations observed in preeclampsia. Ex vivo EC transcriptomics can identify novel mechanisms underlying preeclampsia pathophysiology, with implications for prevention and treatment.

Keywords

RNA sequence; endothelial cells; endothelium; preeclampsia; pregnancy.

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