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Pregnancy outcome relies on the maintenance of immune and metabolic homeostasis at the maternal fetal interface. Maternal and perinatal morbidity and mortality is associated with impaired placental development. Multiple regulatory effects of the endogenous-produced vasoactive intestinal peptide (VIP) on vascular, metabolic and immune functions at the maternal-fetal interface have been reported. Here we studied the involvement of the two primary high affinity receptors for VIP (VPAC1 and VPAC2) on maternal immune response, placental homeostasis and pregnancy outcome. Targeted disruption of each receptor gene led to altered placental structure, vascular and trophoblast functional markers and shaped the functional profiles of macrophages and neutrophils towards a proinflammatory state. Several changes in pregnant mice were receptor specific: ROS production elicited by VIP on neutrophils was selectively dependent on the presence of VPAC1 whereas apoptosis rate was associated with the VPAC2 deletion. In peritoneal macrophages from pregnant mice, levels of MHC-II, TLR2, and IL-10 were selectively altered in VPAC2 receptor-deficient mice, whereas IL-6 gene expression was reduced only in mice lacking VPAC1 receptors. Additionally, MMP9 mRNA in isolated TGCs was reduced in VPAC2 receptor deleted mice, while the percentage of IL-12 cells in post-phagocytosis macrophage cultures was selectively reduced in VPAC2 receptor deficient mice. The results indicate that manipulation of VPAC1 and VPAC2 receptor affects immune, vascular and metabolic environment at the maternal fetal interface. These mouse models offer new approaches to study pregnancy complications adding new perspectives to the development of VPAC receptor-selective drugs.

Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Titel:	VPAC1 and VPAC2 receptor deficiencies negatively influence pregnancy outcome through distinct and overlapping modulations of immune, trophoblast and vascular functions.
Autor/in / Beteiligte Person:	Calo, G ; Hauk, V ; Vota, D ; Van, C ; Condro, M ; Gallino, L ; Ramhorst, R ; Waschek, J ; Pérez Leirós, C
Link:	Zum Volltext
Zeitschrift:	Biochimica et biophysica acta. Molecular basis of disease, Jg. 1869 (2023-02-01), Heft 2, S. 166593
Veröffentlichung:	Amsterdam : Elsevier, 2023
Medientyp:	academicJournal
ISSN:	1879-260X (electronic)
DOI:	10.1016/j.bbadis.2022.166593
Schlagwort:	Animals Female Mice Pregnancy Placenta metabolism Vasoactive Intestinal Peptide metabolism Receptors, Vasoactive Intestinal Polypeptide, Type I genetics Gene Deletion Pregnancy Outcome genetics Receptors, Vasoactive Intestinal Peptide, Type II genetics Trophoblasts metabolism Pregnancy Complications genetics Pregnancy Complications immunology
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article; Research Support, Non-U.S. Gov't Language: English [Biochim Biophys Acta Mol Basis Dis] 2023 Feb; Vol. 1869 (2), pp. 166593. <i>Date of Electronic Publication: </i>2022 Nov 01. MeSH Terms: Pregnancy Outcome* / genetics ; Receptors, Vasoactive Intestinal Peptide, Type II* / genetics ; Trophoblasts* / metabolism ; Pregnancy Complications* / genetics ; Pregnancy Complications* / immunology ; Animals ; Female ; Mice ; Pregnancy ; Placenta / metabolism ; Vasoactive Intestinal Peptide / metabolism ; Receptors, Vasoactive Intestinal Polypeptide, Type I / genetics ; Gene Deletion References: Reproduction. 2009 Oct;138(4):733-42. (PMID: 19633131) ; Front Endocrinol (Lausanne). 2012 Dec 11;3:155. (PMID: 23248616) ; Br J Pharmacol. 2013 Jun;169(3):512-23. (PMID: 23517078) ; Am J Physiol Regul Integr Comp Physiol. 2008 Feb;294(2):R344-51. (PMID: 18032467) ; Brain Behav Immun. 2015 Feb;44:167-175. (PMID: 25305591) ; Br J Pharmacol. 2017 Dec;174(24):4725-4737. (PMID: 28945273) ; Br J Pharmacol. 2012 May;166(1):42-50. (PMID: 21951273) ; Biochim Biophys Acta Mol Basis Dis. 2021 Oct 1;1867(10):166207. (PMID: 34186168) ; Nat Rev Immunol. 2017 Aug;17(8):469-482. (PMID: 28627518) ; PLoS One. 2019 Jan 25;14(1):e0211433. (PMID: 30682157) ; J Vis Exp. 2013 Jul 10;(77):e50586. (PMID: 23892876) ; Endocrinol Jpn. 1980 Dec;27 Suppl 1:71-8. (PMID: 7227322) ; Ann N Y Acad Sci. 2000;921:400-4. (PMID: 11193864) ; Proc Natl Acad Sci U S A. 2021 Oct 12;118(41):. (PMID: 34625492) ; FASEB J. 2019 Feb;33(2):1801-1810. (PMID: 30204500) ; J Immunol. 2015 Aug 1;195(3):1129-38. (PMID: 26071558) ; J Neuroinflammation. 2017 Aug 4;14(1):157. (PMID: 28778207) ; J Neurosci. 2018 Feb 7;38(6):1326-1334. (PMID: 29054877) ; Br J Pharmacol. 2019 Apr;176(7):964-980. (PMID: 30726565) ; Endocrinology. 2004 Mar;145(3):1203-10. (PMID: 14617572) ; Sci Rep. 2016 May 23;6:26364. (PMID: 27212399) ; Am J Reprod Immunol. 2014 Feb;71(2):120-30. (PMID: 24405265) ; J Biol Rhythms. 2014 Oct;29(5):355-69. (PMID: 25252712) ; J Clin Invest. 1996 Jan 1;97(1):202-8. (PMID: 8550835) ; Pancreas. 2011 Aug;40(6):861-71. (PMID: 21697765) ; Mol Hum Reprod. 2015 Dec;21(12):930-41. (PMID: 26502804) ; Front Immunol. 2020 Jan 08;10:2907. (PMID: 31969877) ; Inflamm Res. 2022 Jun;71(5-6):653-668. (PMID: 35445873) ; Placenta. 2017 Aug;56:44-52. (PMID: 28284455) ; Cell Immunol. 2011;267(2):124-32. (PMID: 21295288) ; Biology (Basel). 2022 Mar 11;11(3):. (PMID: 35336804) ; J Immunol. 2014 Sep 15;193(6):3070-9. (PMID: 25135830) ; Ann N Y Acad Sci. 2019 Feb;1437(1):15-21. (PMID: 29740848) ; J Neurosci Res. 2016 Dec;94(12):1472-1487. (PMID: 27717098) ; Cell Adh Migr. 2016 Mar 3;10(1-2):208-25. (PMID: 26933824) ; J Clin Invest. 1994 Nov;94(5):2020-7. (PMID: 7962548) ; Front Endocrinol (Lausanne). 2019 Oct 22;10:729. (PMID: 31695683) ; Hum Reprod. 2017 Jan;32(1):55-64. (PMID: 27932441) ; Sci Rep. 2016 Jan 06;6:18633. (PMID: 26733206) ; Reprod Biol. 2020 Mar;20(1):9-13. (PMID: 31964586) ; J Mol Neurosci. 2015 Jun;56(2):377-87. (PMID: 25904310) ; Nat Rev Endocrinol. 2020 Sep;16(9):479-494. (PMID: 32601352) ; Am J Physiol Regul Integr Comp Physiol. 2003 Nov;285(5):R939-49. (PMID: 12855416) ; J Mol Neurosci. 2018 Sep;66(1):102-113. (PMID: 30105629) ; Endocrinology. 1999 Feb;140(2):917-24. (PMID: 9927324) ; Biomolecules. 2021 Jul 20;11(7):. (PMID: 34356686) Grant Information: P30 HD004612 United States HD NICHD NIH HHS; P50 HD103557 United States HD NICHD NIH HHS; U54 HD087101 United States HD NICHD NIH HHS Contributed Indexing: Keywords: Adverse pregnancy outcome models; Innate response at early pregnancy; Placental homeostasis disruption; VPAC1/VPAC2 knockout mice Substance Nomenclature: 0 (Receptors, Vasoactive Intestinal Peptide, Type II) ; 37221-79-7 (Vasoactive Intestinal Peptide) ; 0 (Receptors, Vasoactive Intestinal Polypeptide, Type I) Entry Date(s): Date Created: 20221103 Date Completed: 20230103 Latest Revision: 20240202 Update Code: 20240202 PubMed Central ID: PMC9772292

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VPAC1 and VPAC2 receptor deficiencies negatively influence pregnancy outcome through distinct and overlapping modulations of immune, trophoblast and vascular functions.