Cytokine concentrations direct endothelial function in pregnancy and preeclampsia

in Journal of Endocrinology
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  • 1 Perinatal Research Laboratories, Department of Obstetrics & Gynecology, University of Wisconsin – Madison, School Medicine and Public Health, Madison, Wisconsin, USA
  • 2 Division of Maternal Fetal Medicine, Department of Obstetrics & Gynecology, University of Wisconsin – Madison, School Medicine and Public Health, Madison, Wisconsin, USA
  • 3 Department of Pediatrics, University of Wisconsin – Madison, School Medicine and Public Health, Madison, Wisconsin, USA

Correspondence should be addressed to D S Boeldt: dsboeldt@wisc.edu

(N Khurshid is now at Promedica Toledo Hospital, Toledo, Ohio, USA)

(D M Berdahl is now at Parkview Health, Fort Wayne, Indiana, USA)

§(D Adu is now at Geisinger Medical Center, Danville, Pennsylvania, USA)

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Abstract

Endothelial dysfunction is a prominent feature of preeclampsia, a hypertensive disorder of pregnancy, and contributes to multiple symptoms characteristic of the syndrome. A myriad of growth factors and cytokines are dysregulated in preeclampsia as compared to normal pregnancy, however, a complete appreciation of the effect of changing concentrations of these factors on endothelial function is lacking. In this study, we evaluate the effect of a variety of growth factors and cytokines on Ca2+ signaling and monolayer integrity. We report that VEGF165, TNFα, EGF, and IL-1β either improve or inhibit Ca2+ signaling depending on dose, whereas TNFα and IL-1β reduce monolayer integrity and bFGF increases monolayer integrity. Additionally, to model the effects of combinations of growth factors and cytokines, we screened for Ca2+ signaling changes in response to 16 dose combinations of VEGF165 and TNFα together. This revealed an optimal combination capable of supporting pregnancy-adapted Ca2+ signaling, and that changes in either VEGF165 or TNFα dose would result in a shift toward suppressed function. This study shows in detail how growth factor or cytokine concentration effects endothelial cell function. Such data can be used to model how changing growth factor and cytokine levels in normal pregnancy may contribute to healthy endothelial function and in preeclampsia may promote endothelial dysfunction. The results of VEGF165 and TNFα combination treatments suggest that more complex growth factor and cytokine combination modeling may be important in order to more accurately understand the effects of circulating factors on the endothelial function.

 

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  • Ampey AC, Boeldt DS, Clemente L, Grummer MA, Yi F, Magness RR & Bird IM 2019 TNF-alpha inhibits pregnancy-adapted Ca(2+) signaling in uterine artery endothelial cells. Molecular and Cellular Endocrinology 488 1424. (https://doi.org/10.1016/j.mce.2019.02.008)

    • Search Google Scholar
    • Export Citation
  • Armant DR, Fritz R, Kilburn BA, Kim YM, Nien JK, Maihle NJ, Romero R & Leach RE 2015 Reduced expression of the epidermal growth factor signaling system in preeclampsia. Placenta 36 27027 8. (https://doi.org/10.1016/j.placenta.2014.12.006)

    • Search Google Scholar
    • Export Citation
  • Bao P, Kodra A, Tomic-Canic M, Golinko MS, Ehrlich HP & Brem H 2009 The role of vascular endothelial growth factor in wound healing. Journal of Surgical Research 153 3473 58. (https://doi.org/10.1016/j.jss.2008.04.023)

    • Search Google Scholar
    • Export Citation
  • Beguin EP, Van Den Eshof BL, Hoogendijk AJ, Nota B, Mertens K, Meijer AB & Van Den Biggelaar M 2019 Integrated proteomic analysis of tumor necrosis factor alpha and interleukin 1beta-induced endothelial inflammation. Journal of Proteomics 192 89101. (https://doi.org/10.1016/j.jprot.2018.08.011)

    • Search Google Scholar
    • Export Citation
  • Boeldt DS & Bird IM 2017 Vascular adaptation in pregnancy and endothelial dysfunction in preeclampsia. Journal of Endocrinology 232 R27R44. (https://doi.org/10.1530/JOE-16-0340)

    • Search Google Scholar
    • Export Citation
  • Boeldt DS, Grummer MA, Magness RR & Bird IM 2014a Altered VEGF-stimulated Ca2+ signaling in part underlies pregnancy-adapted eNOS activity in UAEC. Journal of Endocrinology 223 111. (https://doi.org/10.1530/JOE-14-0252)

    • Search Google Scholar
    • Export Citation
  • Boeldt DS, Hankes AC, Alvarez RE, Khurshid N, Balistreri M, Grummer MA, Yi F & Bird IM 2014b Pregnancy programming and preeclampsia: identifying a human endothelial model to study pregnancy-adapted endothelial function and endothelial adaptive failure in preeclamptic subjects. Advances in Experimental Medicine and Biology 814 2747. (https://doi.org/10.1007/978-1-4939-1031-1_4)

    • Search Google Scholar
    • Export Citation
  • Boeldt DS, Grummer MA, Yi F, Magness RR & Bird IM 2015 Phosphorylation of Ser-279/282 and Tyr-265 positions on Cx43 as possible mediators of VEGF-165 inhibition of pregnancy-adapted Ca2+ burst function in ovine uterine artery endothelial cells. Molecular and Cellular Endocrinology 412 7384. (https://doi.org/10.1016/j.mce.2015.05.030)

    • Search Google Scholar
    • Export Citation
  • Boeldt DS, Krupp J, Yi FX, Khurshid N, Shah DM & Bird IM 2017 Positive versus negative effects of VEGF165 on Ca2+ signaling and NO production in human endothelial cells. American Journal of Physiology: Heart and Circulatory Physiology 312 H173H181. (https://doi.org/10.1152/ajpheart.00924.2015)

    • Search Google Scholar
    • Export Citation
  • Dong W & Yin L 2014 Expression of lipoxin A4, TNFalpha and IL-1beta in maternal peripheral blood, umbilical cord blood and placenta, and their significance in pre-eclampsia. Hypertension in Pregnancy 33 4494 56. (https://doi.org/10.3109/10641955.2014.931419)

    • Search Google Scholar
    • Export Citation
  • Gao F, Sabbineni H, Artham S & Somanath PR 2017 Modulation of long-term endothelial-barrier integrity is conditional to the cross-talk between Akt and Src signaling. Journal of Cellular Physiology 232 25992609. (https://doi.org/10.1002/jcp.25791)

    • Search Google Scholar
    • Export Citation
  • Hammer ES & Cipolla MJ 2015 Cerebrovascular dysfunction in preeclamptic pregnancies. Current Hypertension Reports 17 64. (https://doi.org/10.1007/s11906-015-0575-8)

    • Search Google Scholar
    • Export Citation
  • Hohlagschwandtner M, Knofler M, Ploner M, Zeisler H, Joura EA & Husslein P 2002 Basic fibroblast growth factor and hypertensive disorders in pregnancy. Hypertension in Pregnancy 21 2352 41. (https://doi.org/10.1081/PRG-120016790)

    • Search Google Scholar
    • Export Citation
  • Kaplani K, Koutsi S, Armenis V, Skondra FG, Karantzelis N, Champeris Tsaniras S & Taraviras S 2018 Wound healing related agents: ongoing research and perspectives. Advanced Drug Delivery Reviews 129 242253. (https://doi.org/10.1016/j.addr.2018.02.007)

    • Search Google Scholar
    • Export Citation
  • Krupp J, Boeldt DS, Yi FX, Grummer MA, Bankowski Anaya HA, Shah DM & Bird IM 2013 The loss of sustained Ca(2+) signaling underlies suppressed endothelial nitric oxide production in preeclamptic pregnancies: implications for new therapy. American Journal of Physiology: Heart and Circulatory Physiology 305 H969H9 79. (https://doi.org/10.1152/ajpheart.00250.2013)

    • Search Google Scholar
    • Export Citation
  • Lau SY, Guild SJ, Barrett CJ, Chen Q, Mccowan L, Jordan V & Chamley LW 2013 Tumor necrosis factor-alpha, interleukin-6, and interleukin-10 levels are altered in preeclampsia: a systematic review and meta-analysis. American Journal of Reproductive Immunology 70 4124 27. (https://doi.org/10.1111/aji.12138)

    • Search Google Scholar
    • Export Citation
  • Lecarpentier E & Tsatsaris V 2016 Angiogenic balance (sFlt-1/PlGF) and preeclampsia. Annales d’Endocrinologie 77 97100. (https://doi.org/10.1016/j.ando.2016.04.007)

    • Search Google Scholar
    • Export Citation
  • Mauro AK, Berdahl DM, Khurshid N, Clemente L, Ampey AC, Shah DM, Bird IM & Boeldt DS 2020 Conjugated linoleic acid improves endothelial Ca2+ signaling by blocking growth factor and cytokine-mediated Cx43 phosphorylation. Molecular and Cellular Endocrinology 510 110814. (https://doi.org/10.1016/j.mce.2020.110814)

    • Search Google Scholar
    • Export Citation
  • Montagnana M, Lippi G, Albiero A, Salvagno GL, Franchi M & Guidi GC 2008 Serum pro-inflammatory cytokines in physiological and pre-eclamptic pregnancies. Gynecological Endocrinology 24 11311 6. (https://doi.org/10.1080/09513590801895575)

    • Search Google Scholar
    • Export Citation
  • Morschauser TJ, Ramadoss J, Koch JM, Yi FX, Lopez GE, Bird IM & Magness RR 2014 Local effects of pregnancy on connexin proteins that mediate Ca2+-associated uterine endothelial NO synthesis. Hypertension 63 5895 94. (https://doi.org/10.1161/HYPERTENSIONAHA.113.01171)

    • Search Google Scholar
    • Export Citation
  • Nejabati HR, Latifi Z, Ghasemnejad T, Fattahi A & Nouri M 2017 Placental growth factor (PlGF) as an angiogenic/inflammatory switcher: lesson from early pregnancy losses. Gynecological Endocrinology 33 668674. (https://doi.org/10.1080/09513590.2017.1318375)

    • Search Google Scholar
    • Export Citation
  • Osol G, Ko NL & Mandala M 2017 Altered endothelial nitric oxide signaling as a paradigm for maternal vascular maladaptation in preeclampsia. Current Hypertension Reports 19 82. (https://doi.org/10.1007/s11906-017-0774-6)

    • Search Google Scholar
    • Export Citation
  • Pauli JM & Repke JT 2015 Preeclampsia: short-term and long-term implications. Obstetrics and Gynecology Clinics of North America 42 299313. (https://doi.org/10.1016/j.ogc.2015.01.007)

    • Search Google Scholar
    • Export Citation
  • Rambaldi MP, Weiner E, Mecacci F, Bar J & Petraglia F 2019 Immunomodulation and preeclampsia. Best Practice and Research: Clinical Obstetrics and Gynaecology 60 8796. (https://doi.org/10.1016/j.bpobgyn.2019.06.005)

    • Search Google Scholar
    • Export Citation
  • Sladek SM, Magness RR & Conrad KP 1997 Nitric oxide and pregnancy. American Journal of Physiology 272 R441R4 63. (https://doi.org/10.1152/ajpregu.1997.272.2.R441)

    • Search Google Scholar
    • Export Citation
  • Solan JL & Lampe PD 2014 Specific Cx43 phosphorylation events regulate gap junction turnover in vivo. FEBS Letters 588 1423142 9. (https://doi.org/10.1016/j.febslet.2014.01.049)

    • Search Google Scholar
    • Export Citation
  • Street ME, Seghini P, Fieni S, Ziveri MA, Volta C, Martorana D, Viani I, Gramellini D & Bernasconi S 2006 Changes in interleukin-6 and IGF system and their relationships in placenta and cord blood in newborns with fetal growth restriction compared with controls. European Journal of Endocrinology 155 5675 74. (https://doi.org/10.1530/eje.1.02251)

    • Search Google Scholar
    • Export Citation
  • Szarka A, Rigó J, Lázár L, Beko G & Molvarec A 2010 Circulating cytokines, chemokines and adhesion molecules in normal pregnancy and preeclampsia determined by multiplex suspension array. BMC Immunology 11 59. (https://doi.org/10.1186/1471-2172-11-59)

    • Search Google Scholar
    • Export Citation
  • Umapathy A, Chamley LW & James JL 2020 Reconciling the distinct roles of angiogenic/anti-angiogenic factors in the placenta and maternal circulation of normal and pathological pregnancies. Angiogenesis 23 105117. (https://doi.org/10.1007/s10456-019-09694-w)

    • Search Google Scholar
    • Export Citation
  • Xie C, Yao MZ, Liu JB & Xiong LK 2011 A meta-analysis of tumor necrosis factor-alpha, interleukin-6, and interleukin-10 in preeclampsia. Cytokine 56 55055 9. (https://doi.org/10.1016/j.cyto.2011.09.021)

    • Search Google Scholar
    • Export Citation
  • Yi FX, Boeldt DS, Gifford SM, Sullivan JA, Grummer MA, Magness RR & Bird IM 2010 Pregnancy enhances sustained Ca2+ bursts and endothelial nitric oxide synthase activation in ovine uterine artery endothelial cells through increased connexin 43 function. Biology of Reproduction 82 6675. (https://doi.org/10.1095/biolreprod.109.078253)

    • Search Google Scholar
    • Export Citation
  • Yi FX, Boeldt DS, Magness RR & Bird IM 2011 [Ca2+]i signaling vs. eNOS expression as determinants of NO output in uterine artery endothelium: relative roles in pregnancy adaptation and reversal by VEGF165. American Journal of Physiology: Heart and Circulatory Physiology 300 H1182H11 93. (https://doi.org/10.1152/ajpheart.01108.2010)

    • Search Google Scholar
    • Export Citation
  • Zhang Y, Gu Y, Li H, Lucas MJ & Wang Y 2003 Increased endothelial monolayer permeability is induced by serum from women with preeclampsia but not by serum from women with normal pregnancy or that are not pregnant. Hypertension in Pregnancy 22 99108. (https://doi.org/10.1081/PRG-120017008)

    • Search Google Scholar
    • Export Citation