Activin A causes endothelial dysfunction of mouse aorta and human aortic cells

in Reproduction
Authors:
Courtney Barber The Ritchie Centre, Department of Obstetrics and Gynaecology, School of Clinical Sciences, Monash University, Clayton, Victoria, Australia

Search for other papers by Courtney Barber in
Current site
Google Scholar
PubMed Close
,
Yann Yap The Ritchie Centre, Department of Obstetrics and Gynaecology, School of Clinical Sciences, Monash University, Clayton, Victoria, Australia
The Hudson Institute of Medical Research, Clayton, Victoria, Australia

Search for other papers by Yann Yap in
Current site
Google Scholar
PubMed Close
,
Natalie J Hannan Translational Obstetrics Group, The Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne & Mercy Perinatal, Mercy Hospital for Women, Heidelberg, Victoria, Australia

Search for other papers by Natalie J Hannan in
Current site
Google Scholar
PubMed Close
,
Euan M Wallace The Ritchie Centre, Department of Obstetrics and Gynaecology, School of Clinical Sciences, Monash University, Clayton, Victoria, Australia

Search for other papers by Euan M Wallace in
Current site
Google Scholar
PubMed Close
, and
Sarah A Marshall The Ritchie Centre, Department of Obstetrics and Gynaecology, School of Clinical Sciences, Monash University, Clayton, Victoria, Australia
The Hudson Institute of Medical Research, Clayton, Victoria, Australia

Search for other papers by Sarah A Marshall in
Current site
Google Scholar
PubMed Close
https://orcid.org/0000-0001-7276-1405

Correspondence should be addressed to S A Marshall; Email: sarah.marshall@monash.edu
DOI:
https://doi.org/10.1530/REP-21-0368
Volume/Issue:
Volume 163: Issue 3
Page Range:
145–155
Article Type:
Research Article
Online Publication Date:
14 Feb 2022
Copyright:
© Society for Reproduction and Fertility 2022
Restricted access
Rent on DeepDyve

Sign up for journal news

Preeclampsia is a multisystem hypertensive disorder of pregnancy that remains one of the leading causes of maternal and perinatal morbidity and mortality worldwide. The widespread maternal endothelial dysfunction that underlies preeclampsia is thought to arise from excessive placental production of various factors combined with enhanced oxidative stress. While previous studies have reported elevated activin A in women diagnosed with preeclampsia, whether activin A can cause vascular dysfunction has not yet been thoroughly investigated. Here, we demonstrated that different subtypes of activin A receptors were localised to the endothelial and smooth muscle cells of mouse and human aortae. Then, the aorta of healthy female C57Bl6J mice (n = 8) were incubated for 24 h in various concentrations of recombinant activin A to mimic early pregnancy (5 ng/mL), late pregnancy (20 ng/mL) and preeclampsia (50 ng/mL). Vascular reactivity as assessed by wire myography revealed that only the preeclamptic level of activin A impaired agonist-mediated endothelium-dependent relaxation by reducing the vasodilator prostanoid contribution to relaxation. However, agonist-mediated endothelium-independent mechanisms were unaffected. Further investigations carried out on human aortic endothelial cells suggested that the impairment of aorta relaxation could also be driven by increased endothelial cell permeability, and decreased cell viability, adherence and proliferation. This is the first direct evidence to show that activin A can induce endothelial dysfunction in whole blood vessels, suggesting that at high circulating levels it may contribute to the widespread endothelial dysfunction in women with preeclampsia.

Reproduction is committed to supporting researchers in demonstrating the impact of their articles published in the journal.

The two types of article metrics we measure are (i) more traditional full-text views and pdf downloads, and (ii) Altmetric data, which shows the wider impact of articles in a range of non-traditional sources, such as social media.

More information is on the Reasons to publish page.

Sept 2018 onwards Past Year Past 30 Days
Full Text Views 650 164 2
PDF Downloads 410 62 1

 

  • Collapse
  • Expand
Print ISSN:
1470-1626
Online ISSN:
1741-7899

  • Barden A, Beilin LJ, Ritchie J, Walters BN & Michael CA 1994 Plasma and urinary endothelin 1, prostacyclin metabolites and platelet consumption in pre-eclampsia and essential hypertensive pregnancy. Blood Pressure 3 38–46. (https://doi.org/10.3109/08037059409101520)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Benschop L, Duvekot JJ & Roeters van Lennep JE 2019 Future risk of cardiovascular disease risk factors and events in women after a hypertensive disorder of pregnancy. Heart 105 1273–1278. (https://doi.org/10.1136/heartjnl-2018-313453)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Bersinger NA, Smarason AK, Muttukrishna S, Groome NP & Redman CW 2003 Women with preeclampsia have increased serum levels of pregnancy-associated plasma protein A (PAPP-A), inhibin A, activin A and soluble E-selectin. Hypertension in Pregnancy 22 45–55. (https://doi.org/10.1081/PRG-120016794)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Bloise E, Ciarmela P, Dela Cruz C, Luisi S, Petraglia F & Reis FM 2019 Activin A in mammalian physiology. Physiological Reviews 99 739–780. (https://doi.org/10.1152/physrev.00002.2018)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Breit S, Ashman K, Wilting J, Rössler J, Hatzi E, Fotsis T & Schweigerer L 2000 The N-myc oncogene in human neuroblastoma cells: down-regulation of an angiogenesis inhibitor identified as activin A. Cancer Research 60 4596–4601.

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Cartwright JE, Fraser R, Leslie K, Wallace AE & James JL 2010 Remodelling at the maternal-fetal interface: relevance to human pregnancy disorders. Reproduction 140 803–813. (https://doi.org/10.1530/REP-10-0294)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Chavarría ME, Lara-González L, González-Gleason A, García-Paleta Y, Vital-Reyes VS & Reyes A 2003 Prostacyclin/thromboxane early changes in pregnancies that are complicated by preeclampsia. American Journal of Obstetrics and Gynecology 188 986–992. (https://doi.org/10.1067/mob.2003.203)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • D’Antona D, Reis FM, Benedetto C, Evans LW, Groome NP, de Kretser DM, Wallace EM & Petraglia F 2000 Increased maternal serum activin A but not follistatin levels in pregnant women with hypertensive disorders. Journal of Endocrinology 165 157–162. (https://doi.org/10.1677/joe.0.1650157)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Diesch CH, Holzgreve W, Hahn S & Zhong XY 2006 Comparison of activin A and cell-free fetal DNA levels in maternal plasma from patients at high risk for preeclampsia. Prenatal Diagnosis 26 1267–1270. (https://doi.org/10.1002/pd.1606)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Downing I, Shepherd GL & Lewis PJ 1980 Reduced prostacyclin production in pre-eclampsia. Lancet 2 1374. (https://doi.org/10.1016/s0140-6736(8092443-5)

  • Florio P, Reis FM, Severi FM, Luisi S, Imperatore A, Palumbo MA, Bagnoli F, Gioffre W & Petraglia F 2006 Umbilical cord serum activin A levels are increased in pre-eclampsia with impaired blood flow in the uteroplacental and fetal circulation. Placenta 27 432–437. (https://doi.org/10.1016/j.placenta.2005.04.008)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Fowler PA, Evans LW, Groome NP, Templeton A & Knight PG 1998 A longitudinal study of maternal serum inhibin-A, inhibin-B, activin-A, activin-AB, pro-alphaC and follistatin during pregnancy. Human Reproduction 13 3530–3536. (https://doi.org/10.1093/humrep/13.12.3530)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Goulopoulou S & Davidge ST 2015 Molecular mechanisms of maternal vascular dysfunction in preeclampsia. Trends in Molecular Medicine 21 88–97. (https://doi.org/10.1016/j.molmed.2014.11.009)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Gurusinghe S, Wallace EM & Lim R 2014 The relationship between activin A and anti-angiogenic factors in the development of pre-eclampsia. Pregnancy Hypertension 4 3–6. (https://doi.org/10.1016/j.preghy.2013.09.002)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Harrison CA, Chan KL & Robertson DM 2006 Activin-A binds follistatin and type II receptors through overlapping binding sites: generation of mutants with isolated binding activities. Endocrinology 147 2744–2753. (https://doi.org/10.1210/en.2006-0131)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Hobson SR, Acharya R, Lim R, Chan ST, Mockler J & Wallace EM 2016 Role of activin A in the pathogenesis of endothelial cell dysfunction in preeclampsia. Pregnancy Hypertension 6 130–133. (https://doi.org/10.1016/j.preghy.2016.03.001)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kaneda H, Arao T, Matsumoto K, De Velasco MA, Tamura D, Aomatsu K, Kudo K, Sakai K, Nagai T & Fujita Y et al.2011 Activin A inhibits vascular endothelial cell growth and suppresses tumour angiogenesis in gastric cancer. British Journal of Cancer 105 1210–1217. (https://doi.org/10.1038/bjc.2011.348)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Karumanchi SA 2016 Angiogenic factors in preeclampsia: from diagnosis to therapy. Hypertension 67 1072–1079. (https://doi.org/10.1161/HYPERTENSIONAHA.116.06421)

  • Langston-Cox A, Leo CH, Tare M, Wallace EM & Marshall SA 2020 Sulforaphane improves vascular reactivity in mouse and human arteries after ‘preeclamptic-like’ injury. Placenta 101 242–250. (https://doi.org/10.1016/j.placenta.2020.09.001)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Lim R, Acharya R, Delpachitra P, Hobson S, Sobey CG, Drummond GR & Wallace EM 2015 Activin and NADPH-oxidase in preeclampsia: insights from in vitro and murine studies. American Journal of Obstetrics and Gynecology 212 86.e1–86. e 12. (https://doi.org/10.1016/j.ajog.2014.07.021)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Lowe SA, Bowyer L, Lust K, McMahon LP, Morton M, North RA, Paech M & Said JM 2015 SOMANZ guidelines for the management of hypertensive disorders of pregnancy 2014. Australian and New Zealand Journal of Obstetrics and Gynaecology 55 e1–29. (https://doi.org/10.1111/ajo.12399)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Marshall SA, O’Sullivan K, Ng HH, Bathgate RAD, Parry LJ, Hossain MA & Leo CH 2017 B7-33 replicates the vasoprotective functions of human relaxin-2 (serelaxin). European Journal of Pharmacology 807 190–197. (https://doi.org/10.1016/j.ejphar.2017.05.005)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Marshall SA, Senadheera SN, Jelinic M, O’Sullivan K, Parry LJ & Tare M 2018 Relaxin deficiency leads to uterine artery dysfunction during pregnancy in mice. Frontiers in Physiology 9 255. (https://doi.org/10.3389/fphys.2018.00255)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Marshall SA, Qin CX, Jelinic M, O’Sullivan K, Deo M, Walsh J, Li M, Parry LJ, Ritchie RH & Leo CH 2020 The novel small-molecule annexin-A1 mimetic, compound 17b, elicits vasoprotective actions in streptozotocin-induced diabetic mice. International Journal of Molecular Sciences 21 E1384. (https://doi.org/10.3390/ijms21041384)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Maynard SE, Min JY, Merchan J, Lim KH, Li J, Mondal S, Libermann TA, Morgan JP, Sellke FW & Stillman IE et al.2003 Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. Journal of Clinical Investigation 111 649–658. (https://doi.org/10.1172/JCI17189)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • McCarthy SA & Bicknell R 1993 Inhibition of vascular endothelial cell growth by activin-A. Journal of Biological Chemistry 268 23066–23071. (https://doi.org/10.1016/S0021-9258(1949426-X)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Mol BWJ, Roberts CT, Thangaratinam S, Magee LA, de Groot CJM & Hofmeyr GJ 2016 Pre-eclampsia. Lancet 387 999–1011. (https://doi.org/10.1016/S0140-6736(1500070-7)

  • Muttukrishna S, Hyett J, Paine M, Moodley J, Groome N & Rodeck C 2006 Uterine vein and maternal urinary levels of activin A and inhibin A in pre-eclampsia patients. Clinical Endocrinology 64 469–473. (https://doi.org/10.1111/j.1365-2265.2006.02476.x)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Nakaoka T, Gonda K, Ogita T, Otawara-Hamamoto Y, Okabe F, Kira Y, Harii K, Miyazono K, Takuwa Y & Fujita T 1997 Inhibition of rat vascular smooth muscle proliferation in vitro and in vivo by bone morphogenetic protein-2. Journal of Clinical Investigation 100 2824–2832. (https://doi.org/10.1172/JCI119830)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Nüsing RM & Barsig J 1999 Induction of prostanoid, nitric oxide, and cytokine formation in rat bone marrow derived macrophages by activin A. British Journal of Pharmacology 127 919–926. (https://doi.org/10.1038/sj.bjp.0702626)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Park HJ, Shim SS & Cha DH 2015 Combined screening for early detection of pre-eclampsia. International Journal of Molecular Sciences 16 17952–17974. (https://doi.org/10.3390/ijms160817952)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Pawlowski JE, Taylor DS, Valentine M, Hail ME, Ferrer P, Kowala MC & Molloy CJ 1997 Stimulation of activin A expression in rat aortic smooth muscle cells by thrombin and angiotensin II correlates with neointimal formation in vivo. Journal of Clinical Investigation 100 639–648. (https://doi.org/10.1172/JCI119575)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Petraglia F, De Vita D, Gallinelli A, Aguzzoli L, Genazzani AR, Romero R & Woodruff TK 1995 Abnormal concentration of maternal serum activin-A in gestational diseases. Journal of Clinical Endocrinology and Metabolism 80 558–561. (https://doi.org/10.1210/jcem.80.2.7852520)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Powe CE, Levine RJ & Karumanchi SA 2011 Preeclampsia, a disease of the maternal endothelium: the role of antiangiogenic factors and implications for later cardiovascular disease. Circulation 123 2856–2869. (https://doi.org/10.1161/CIRCULATIONAHA.109.853127)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Reddy A, Suri S, Sargent IL, Redman CW & Muttukrishna S 2009 Maternal circulating levels of activin A, inhibin A, sFlt-1 and endoglin at parturition in normal pregnancy and pre-eclampsia. PLoS ONE 4 e4453. (https://doi.org/10.1371/journal.pone.0004453)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Remuzzi G, Marchesi D, Zoja C, Muratore D, Mecca G, Misiani R, Rossi E, Barbato M, Capetta P & Donati MB et al.1980 Reduced umbilical and placental vascular prostacyclin in severe pre-eclampsia. Prostaglandins 20 105–110. (https://doi.org/10.1016/0090-6980(8090010-6)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Seo HR, Jeong HE, Joo HJ, Choi SC, Park CY, Kim JH, Choi JH, Cui LH, Hong SJ & Chung S et al.2016 Intrinsic FGF2 and FGF5 promotes angiogenesis of human aortic endothelial cells in 3D microfluidic angiogenesis system. Scientific Reports 6 28832. (https://doi.org/10.1038/srep28832)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Shahul S, Ramadan H, Nizamuddin J, Mueller A, Patel V, Dreixler J, Tung A, Lang RM, Weinert L & Nasim R et al.2018 Activin A and late postpartum cardiac dysfunction among women with hypertensive disorders of pregnancy. Hypertension 72 188–193. (https://doi.org/10.1161/HYPERTENSIONAHA.118.10888)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Smith GC, Stenhouse EJ, Crossley JA, Aitken DA, Cameron AD & Connor JM 2002 Early pregnancy levels of pregnancy-associated plasma protein A and the risk of intrauterine growth restriction, premature birth, preeclampsia, and stillbirth. Journal of Clinical Endocrinology and Metabolism 87 1762–1767. (https://doi.org/10.1210/jcem.87.4.8430)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Smyth EM, Grosser T, Wang M, Yu Y & FitzGerald GA 2009 Prostanoids in health and disease. Journal of Lipid Research 50 (Supplement) S423–S428. (https://doi.org/10.1194/jlr.R800094-JLR200)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Staff AC 2019 The two-stage placental model of preeclampsia: an update. Journal of Reproductive Immunology 134–135 1–10. (https://doi.org/10.1016/j.jri.2019.07.004)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Stoikos CJ, Salamonsen LA, Hannan NJ, O’Connor AE, Rombauts L & Dimitriadis E 2010 Activin A regulates trophoblast cell adhesive properties: implications for implantation failure in women with endometriosis-associated infertility. Human Reproduction 25 1767–1774. (https://doi.org/10.1093/humrep/deq097)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Venkatesha S, Toporsian M, Lam C, Hanai J-i, Mammoto T, Kim YM, Bdolah Y, Lim KH, Yuan HT & Libermann TA et al.2006 Soluble endoglin contributes to the pathogenesis of preeclampsia. Nature Medicine 12 642–649. (https://doi.org/10.1038/nm1429)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Walsh SW 2004 Eicosanoids in preeclampsia. Prostaglandins, Leukotrienes, and Essential Fatty Acids 70 223–232. (https://doi.org/10.1016/j.plefa.2003.04.010)

  • Wang Q, Keutmann HT, Schneyer AL & Sluss PM 2000 Analysis of human follistatin structure: identification of two discontinuous N-terminal sequences coding for activin A binding and structural consequences of activin binding to native proteins. Endocrinology 141 3183–3193. (https://doi.org/10.1210/endo.141.9.7675)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Wijayarathna R & de Kretser DM 2016 Activins in reproductive biology and beyond. Human Reproduction Update 22 342–357. (https://doi.org/10.1093/humupd/dmv058)

  • Wu P, Haththotuwa R, Kwok CS, Babu A, Kotronias RA, Rushton C, Zaman A, Fryer AA, Kadam U & Chew-Graham CA et al.2017 Preeclampsia and future cardiovascular health: a systematic review and meta-analysis. Circulation: Cardiovascular Quality and Outcomes 10 e003497. (https://doi.org/10.1161/CIRCOUTCOMES.116.003497)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Yamashita T, Shimizu T & Ogata E 1991 Activin A/erythroid differentiation factor induces thromboxane A2 synthetic activity in murine erythroleukemia cells. Journal of Biological Chemistry 266 3888–3892. (https://doi.org/10.1016/S0021-9258(1967877-4)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Yong HE, Murthi P, Wong MH, Kalionis B, Cartwright JE, Brennecke SP & Keogh RJ 2015 Effects of normal and high circulating concentrations of activin A on vascular endothelial cell functions and vasoactive factor production. Pregnancy Hypertension 5 346–353. (https://doi.org/10.1016/j.preghy.2015.09.006)

    • PubMed
    • Search Google Scholar
    • Export Citation