Academic Journal
Προβολή σε EDS
Συνδεδεμένο Πλήρες Κείμενο

Vascular Endothelial Growth Factor Receptors 1 and 3 Mediate Placental Trophoblast Leptin Production in Preeclampsia, Inducing Vascular Dysfunction.

Λεπτομέρειες βιβλιογραφικής εγγραφής
Τίτλος: Vascular Endothelial Growth Factor Receptors 1 and 3 Mediate Placental Trophoblast Leptin Production in Preeclampsia, Inducing Vascular Dysfunction.
Συγγραφείς: Elgazzaz M; Department of Physiology (M.E., S.O., D.M., E.M., G.C., K.B., G.H., D.V.I., J.L.F.), Medical College of Georgia at Augusta University., Ogbi S; Department of Physiology (M.E., S.O., D.M., E.M., G.C., K.B., G.H., D.V.I., J.L.F.), Medical College of Georgia at Augusta University., Moronge D; Department of Physiology (M.E., S.O., D.M., E.M., G.C., K.B., G.H., D.V.I., J.L.F.), Medical College of Georgia at Augusta University., Mellott E; Department of Physiology (M.E., S.O., D.M., E.M., G.C., K.B., G.H., D.V.I., J.L.F.), Medical College of Georgia at Augusta University., Cooper G; Department of Physiology (M.E., S.O., D.M., E.M., G.C., K.B., G.H., D.V.I., J.L.F.), Medical College of Georgia at Augusta University., Backer K; Department of Physiology (M.E., S.O., D.M., E.M., G.C., K.B., G.H., D.V.I., J.L.F.), Medical College of Georgia at Augusta University., Brawley A; Department of Obstetrics and Gynecology (A.B., P.C.W., J.M., J.L.F.), Medical College of Georgia at Augusta University., Hernendez G; Department of Physiology (M.E., S.O., D.M., E.M., G.C., K.B., G.H., D.V.I., J.L.F.), Medical College of Georgia at Augusta University., Hitchings J; Department of Pathology (J.H., L.V.Z., S.K.), Medical College of Georgia at Augusta University., Valesquez Zarate L; Department of Pathology (J.H., L.V.Z., S.K.), Medical College of Georgia at Augusta University., Kavuri S; Department of Pathology (J.H., L.V.Z., S.K.), Medical College of Georgia at Augusta University., Lee TJ; Department of Cellular Biology and Anatomy (T.J.L.), Medical College of Georgia at Augusta University., Ilatovskaya DV; Department of Physiology (M.E., S.O., D.M., E.M., G.C., K.B., G.H., D.V.I., J.L.F.), Medical College of Georgia at Augusta University., Woodham PC; Department of Obstetrics and Gynecology (A.B., P.C.W., J.M., J.L.F.), Medical College of Georgia at Augusta University., Maher J; Department of Obstetrics and Gynecology (A.B., P.C.W., J.M., J.L.F.), Medical College of Georgia at Augusta University., Annex BH; Vascular Biology Center and Department of Medicine (B.H.A.), Medical College of Georgia at Augusta University., Faulkner JL; Department of Physiology (M.E., S.O., D.M., E.M., G.C., K.B., G.H., D.V.I., J.L.F.), Medical College of Georgia at Augusta University.; Department of Obstetrics and Gynecology (A.B., P.C.W., J.M., J.L.F.), Medical College of Georgia at Augusta University.
Πηγή: Arteriosclerosis, thrombosis, and vascular biology [Arterioscler Thromb Vasc Biol] 2026 Sep; Vol. 46 (9), pp. e324143. Date of Electronic Publication: 2026 Jul 09.
Τύπος έκδοσης: Journal Article
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: Lippincott Williams & Wilkins Country of Publication: United States NLM ID: 9505803 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1524-4636 (Electronic) Linking ISSN: 10795642 NLM ISO Abbreviation: Arterioscler Thromb Vasc Biol Subsets: MEDLINE
Imprint Name(s): Publication: 1998- : Baltimore, Md. : Lippincott Williams & Wilkins
Original Publication: Dallas, TX : American Heart Association, c1995-
Ιατρικοί όροι (MeSH): Leptin*/metabolism , Pre-Eclampsia*/physiopathology , Pre-Eclampsia*/metabolism , Vascular Endothelial Growth Factor Receptor-1*/metabolism , Vascular Endothelial Growth Factor Receptor-1*/administration & dosage , Trophoblasts*/metabolism , Trophoblasts*/drug effects, Receptors, Leptin/metabolism ; Pregnancy Proteins/metabolism ; Vascular Endothelial Growth Factor A/metabolism ; Vascular Endothelial Growth Factor A/pharmacology ; Female ; Animals ; Pregnancy ; Humans ; Placenta Growth Factor ; Cells, Cultured ; Mice, Inbred C57BL ; Disease Models, Animal ; Mice ; Signal Transduction
Περίληψη: Background: Heightened sFlt-1 (soluble FMS-like tyrosine kinase-1) level is a hallmark of preeclampsia patients and induces a state of angiogenic imbalance by sequestering free VEGF (vascular endothelial growth factor) and PlGF (placental growth factor). The receptors for VEGF and PlGF, membrane-bound VEGFR (VEGF receptor), are expressed in placental trophoblast cells, but their functions in this cell type are largely unknown. Placental production of leptin significantly increases in preeclampsia, and we recently showed that leptin induces placental and vascular endothelial dysfunction in pregnancy. We hypothesized that inappropriately high sFlt-1 in preeclampsia leads to an increase in trophoblast leptin production.
Methods: We treated human placental explants, trophoblast, and adipose cells with sFlt-1. We also infused pregnant mice with sFlt-1 via osmotic minipump from mid-late gestation.
Results: We show an increase in leptin peptide production, which is ablated by coadministration with either VEGF or PlGF (placental growth factor). We further demonstrate that VEGFR1 and 3, not R2, expressions are predominant in human trophoblasts and that reducing activation of these receptors mediates trophoblast leptin production. In pregnant mice, we show that sFlt-1 infusion induces vascular endothelial dysfunction in association with significantly elevated plasma leptin levels. In pregnant sFlt-1-infused mice, treatment with a leptin receptor antagonist significantly ablated vascular endothelial dysfunction.
Conclusions: Collectively, these data indicate that angiogenic imbalance in preeclampsia impacts placental trophoblast endocrine function by suppressing VEGFR1 and 3 activation, resulting in leptin overproduction. Furthermore, sFlt-1 induces vascular endothelial dysfunction in mice dependent on leptin receptor activation.
Competing Interests: None.
Σχόλια: Update of: bioRxiv. 2025 Jun 01:2025.05.27.656489. doi: 10.1101/2025.05.27.656489.. (PMID: 40501588)
References: Fetal Pediatr Pathol. 2025 Nov-Dec;44(6):573-582. (PMID: 40970739)
Biochem Biophys Res Commun. 2000 Jul 21;274(1):117-23. (PMID: 10903905)
Hypertension. 2008 Nov;52(5):873-80. (PMID: 18824660)
Eur Rev Med Pharmacol Sci. 2024 Jul;28(13):3922-3933. (PMID: 39012231)
Mol Biol Cell. 2007 Feb;18(2):617-26. (PMID: 17135290)
J Cell Mol Med. 2018 Feb;22(2):716-727. (PMID: 29160594)
Placenta. 2005 Jan;26(1):47-52. (PMID: 15664410)
Circulation. 2015 Dec 1;132(22):2134-45. (PMID: 26362633)
PLoS Comput Biol. 2024 Feb 7;20(2):e1011798. (PMID: 38324585)
N Engl J Med. 2004 Feb 12;350(7):672-83. (PMID: 14764923)
PLoS One. 2015 Apr 10;10(4):e0119547. (PMID: 25860260)
Placenta. 2005 Feb-Mar;26(2-3):210-7. (PMID: 15708122)
Reprod Sci. 2013 Sep;20(9):1083-9. (PMID: 23439619)
Am J Physiol Heart Circ Physiol. 2024 Jul 1;327(1):H118-H130. (PMID: 38758130)
FASEB J. 2008 Apr;22(4):966-81. (PMID: 18024835)
Ann Endocrinol (Paris). 2016 Jun;77(2):97-100. (PMID: 27130072)
IUBMB Life. 2001 Jul;52(1-2):61-6. (PMID: 11795595)
Hypertension. 2022 Jul;79(7):1536-1547. (PMID: 35510543)
Int J Mol Sci. 2022 Nov 09;23(22):. (PMID: 36430232)
Biol Reprod. 2000 Jul;63(1):274-80. (PMID: 10859269)
Eur J Med Res. 2024 Dec 31;29(1):642. (PMID: 39741314)
J Endocrinol. 2017 Jan;232(1):R27-R44. (PMID: 27729465)
Carcinogenesis. 2013 Sep;34(9):1976-83. (PMID: 23661635)
Mol Hum Reprod. 2001 Feb;7(2):205-10. (PMID: 11160848)
Arterioscler Thromb Vasc Biol. 2025 May;45(5):585-599. (PMID: 40177777)
J Cell Mol Med. 2023 Apr;27(8):1083-1094. (PMID: 36950780)
Eur J Pharmacol. 2025 Jan 5;986:177138. (PMID: 39551338)
Stem Cells Dev. 2011 Dec;20(12):2139-51. (PMID: 21671749)
Nat Commun. 2023 Feb 9;14(1):632. (PMID: 36759523)
Am J Physiol Regul Integr Comp Physiol. 2013 Jan 15;304(2):R130-5. (PMID: 23193111)
Placenta. 2021 Nov;115:87-96. (PMID: 34583270)
Pregnancy Hypertens. 2024 Mar;35:66-72. (PMID: 38245918)
Am J Obstet Gynecol. 2024 Sep;231(3):363.e1-363.e11. (PMID: 38825028)
Circ Res. 2017 Jan 20;120(2):282-295. (PMID: 27974423)
PLoS One. 2013;8(1):e54153. (PMID: 23326589)
Cardiovasc Res. 2021 Jul 7;117(8):1877-1890. (PMID: 33067626)
Placenta. 2013 Oct;34(10):949-52. (PMID: 23899470)
Nat Rev Immunol. 2006 Aug;6(8):584-94. (PMID: 16868549)
Lancet Glob Health. 2025 Apr;13(4):e626-e634. (PMID: 40064189)
Am J Obstet Gynecol. 2002 Jul;187(1):127-36. (PMID: 12114900)
Cancer Res. 2004 Nov 1;64(21):7822-35. (PMID: 15520188)
Am J Reprod Immunol. 1998 Aug;40(2):102-11. (PMID: 9764352)
Am J Obstet Gynecol. 2004 Oct;191(4):1240-6. (PMID: 15507947)
PLoS One. 2013 Apr 23;8(4):e61857. (PMID: 23626741)
Life (Basel). 2023 Jan 03;13(1):. (PMID: 36676079)
Hypertension. 2016 Feb;67(2):415-23. (PMID: 26711737)
Am J Reprod Immunol. 2010 Jun;63(6):534-43. (PMID: 20331588)
EMBO Mol Med. 2013 Sep;5(9):1415-30. (PMID: 23853117)
Placenta. 2024 Dec;158:253-262. (PMID: 39522465)
Am J Physiol Cell Physiol. 2024 Sep 1;327(3):C646-C660. (PMID: 39010840)
Hypertension. 2025 May;82(5):883-893. (PMID: 40171652)
Endocrinology. 2022 Aug 1;163(8):. (PMID: 35772781)
Reprod Sci. 2020 Oct;27(10):1932-1942. (PMID: 32548805)
Biomaterials. 2012 Apr;33(12):3475-84. (PMID: 22322198)
Proc Natl Acad Sci U S A. 1993 Nov 15;90(22):10705-9. (PMID: 8248162)
Hum Reprod. 1996 May;11(5):1090-8. (PMID: 8671397)
Proc Natl Acad Sci U S A. 2011 Jan 25;108(4):1197-8. (PMID: 21233419)
Am J Hypertens. 2011 Sep;24(9):964-9. (PMID: 21677700)
Circulation. 2011 Jun 21;123(24):2856-69. (PMID: 21690502)
J Biol Chem. 1997 Nov 28;272(48):30546-51. (PMID: 9374549)
Int J Mol Sci. 2021 Apr 27;22(9):. (PMID: 33925454)
Vasc Cell. 2011 Jul 13;3(1):15. (PMID: 21752276)
NEJM Evid. 2022 Dec;1(12):EVIDoa2200161. (PMID: 38319832)
Hypertension. 2015 Mar;65(3):594-9. (PMID: 25510827)
Ultrasound Obstet Gynecol. 2025 Mar;65(3):317-324. (PMID: 39888184)
Biochem Biophys Res Commun. 2020 Jul 5;527(4):1064-1071. (PMID: 32448504)
Obstet Gynecol. 2020 Jun;135(6):e237-e260. (PMID: 32443079)
Hypertension. 2020 Dec;76(6):1808-1816. (PMID: 33012203)
Am J Physiol Heart Circ Physiol. 2021 Jul 1;321(1):H77-H111. (PMID: 33989082)
PLoS One. 2013 Sep 30;8(9):e75759. (PMID: 24098721)
Hypertension. 2013 Dec;62(6):1046-54. (PMID: 24060885)
Circ Res. 2019 Mar 29;124(7):1094-1112. (PMID: 30920918)
Clin Chim Acta. 2016 Jul 1;458:133-7. (PMID: 27154800)
Biochem Biophys Res Commun. 1998 Jan 14;242(2):345-50. (PMID: 9446797)
Placenta. 2006 Sep-Oct;27(9-10):939-58. (PMID: 16490251)
Hypertension. 2015 Dec;66(6):1251-9. (PMID: 26416849)
Placenta. 2005 Aug;26(7):563-73. (PMID: 15993706)
Nat Commun. 2022 Oct 14;13(1):6020. (PMID: 36241646)
Pregnancy Hypertens. 2022 Mar;27:148-169. (PMID: 35066406)
Semin Reprod Endocrinol. 1998;16(1):5-15. (PMID: 9654603)
Womens Health (Lond). 2023 Jan-Dec;19:17455057231213272. (PMID: 38047453)
Cardiovasc J Afr. 2016 Mar-Apr;27(2):71-8. (PMID: 27213853)
Hypertension. 2018 Dec;72(6):1397-1406. (PMID: 30571230)
MCN Am J Matern Child Nurs. 2019 May/Jun;44(3):170. (PMID: 31033586)
J Hum Hypertens. 2017 Dec;31(12):782-786. (PMID: 29115294)
Pregnancy Hypertens. 2019 Jan;15:78-83. (PMID: 30825932)
Bull Exp Biol Med. 2013 Apr;154(6):792-5. (PMID: 23658926)
Pflugers Arch. 2004 Feb;447(5):480-9. (PMID: 12750891)
Am J Physiol Heart Circ Physiol. 2006 Sep;291(3):H1421-8. (PMID: 16603699)
Biomed Res Int. 2013;2013:298401. (PMID: 24167814)
Cardiovasc Res. 2022 Oct 21;118(13):2833-2846. (PMID: 34849650)
Int J Gynaecol Obstet. 2007 Aug;98(2):110-4. (PMID: 17585917)
Am J Hypertens. 2010 Aug;23(8):911-6. (PMID: 20431529)
J Endocrinol. 2007 Sep;194(3):611-9. (PMID: 17761900)
Biomolecules. 2021 Feb 10;11(2):. (PMID: 33578823)
Placenta. 2014 Mar;35(3):202-6. (PMID: 24529946)
Med J Obstet Gynecol. 2013 Sep 23;1(2):. (PMID: 25414911)
Expert Opin Ther Targets. 2021 May;25(5):381-391. (PMID: 34098826)
Hypertension. 2019 Sep;74(3):678-686. (PMID: 31327274)
Circ Res. 2023 Mar 17;132(6):674-689. (PMID: 36815487)
Cells. 2022 Aug 28;11(17):. (PMID: 36078086)
Hypertension. 2016 May;67(5):1020-8. (PMID: 26953321)
Grant Information: R00 HL146948 United States HL NHLBI NIH HHS; R01 DK134695 United States DK NIDDK NIH HHS; R01 HL169576 United States HL NHLBI NIH HHS; U54 HL169191 United States HL NHLBI NIH HHS
Contributed Indexing: Keywords: adipose tissue; body mass index; fetal death; leptin; trophoblasts
Substance Nomenclature: 0 (Leptin)
EC 2.7.10.1 (Vascular Endothelial Growth Factor Receptor-1)
144589-93-5 (Placenta Growth Factor)
0 (PGF protein, human)
EC 2.7.10.1 (FLT1 protein, human)
0 (Pgf protein, mouse)
EC 2.7.10.1 (Flt1 protein, mouse)
0 (Receptors, Leptin)
0 (Pregnancy Proteins)
0 (Vascular Endothelial Growth Factor A)
0 (LEP protein, human)
Entry Date(s): Date Created: 20260709 Date Completed: 20260826 Latest Revision: 20260922
Update Code: 20260922
PubMed Central ID: PMC13353211
DOI: 10.1161/ATVBAHA.125.324143
PMID: 42422950
Βάση Δεδομένων: MEDLINE
Περιγραφή
ISSN:1524-4636
DOI:10.1161/ATVBAHA.125.324143