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Diminished vasculogenesis under inflammatory conditions is mediated by Activin A

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Abstract

Severe inflammatory stress often leads to vessel rarefaction and fibrosis, resulting in limited tissue recovery. However, signaling pathways mediating these processes are not completely understood. Patients with ischemic and inflammatory conditions have increased systemic Activin A level, which frequently correlates with the severity of pathology. Yet, Activin A’s contribution to disease progression, specifically to vascular homeostasis and remodeling, is not well defined. This study investigated vasculogenesis in an inflammatory environment with an emphasis on Activin A’s role. Exposure of endothelial cells (EC) and perivascular cells (adipose stromal cells, ASC) to inflammatory stimuli (represented by blood mononuclear cells from healthy donors activated with lipopolysaccharide, aPBMC) dramatically decreased EC tubulogenesis or caused vessel rarefaction compared to control co-cultures, concurrent with increased Activin A secretion. Both EC and ASC upregulated Inhibin Ba mRNA and Activin A secretion in response to aPBMC or their secretome. We identified TNFα (in EC) and IL-1β (in EC and ASC) as the exclusive inflammatory factors, present in aPBMC secretome, responsible for induction of Activin A. Similar to ASC, brain and placental pericytes upregulated Activin A in response to aPBMC and IL-1β, but not TNFα. Both these cytokines individually diminished EC tubulogenesis. Blocking Activin A with neutralizing IgG mitigated detrimental effects of aPBMC or TNFα/IL-1β on tubulogenesis in vitro and vessel formation in vivo. This study delineates the signaling pathway through which inflammatory cells have a detrimental effect on vessel formation and homeostasis, and highlights the central role of Activin A in this process. Transitory interference with Activin A during early phases of inflammatory or ischemic insult, with neutralizing antibodies or scavengers, may benefit vasculature preservation and overall tissue recovery.

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Abbreviations

EC:

Endothelial cell

CBEC:

Cord-blood endothelial cell

HUVEC:

Human umbilical vein endothelial cell

HMVEC:

Human cardiac microvascular endothelial cell

ASC:

Adipose stromal cells

PBMC:

Peripheral blood mononuclear cells

aPBMC:

Activated peripheral blood mononuclear cells

TNFα:

Tumor necrosis factor alpha

IL-1β:

Interleukin-1 beta

IFNγ:

Interferon gamma

IL-6:

Interleukin 6

LPS:

Lipopolysaccharide

FST:

Follistatin

FSTL3:

Follistatin-like 3

References

  1. Vos T, Abajobir AA, Abate KH, Abbafati C, Abbas KM, Abd-Allah F, Abdulkader RS, Abdulle AM, Abebo TA, Abera SF, Aboyans V (2017) Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016 (2017). Lancet 390(10100):1211–1259. https://doi.org/10.1016/s0140-6736(17)32154-2

    Article  Google Scholar 

  2. Cuijpers I, Simmonds SJ, van Bilsen M, Czarnowska E, González Miqueo A, Heymans S, Kuhn AR, Mulder P, Ratajska A, Jones EAV, Brakenhielm E (2020) Microvascular and lymphatic dysfunction in HFpEF and its associated comorbidities. Basic Res Cardiol 115(4):39. https://doi.org/10.1007/s00395-020-0798-y

    Article  PubMed  PubMed Central  Google Scholar 

  3. Goligorsky MS (2010) Microvascular rarefaction: the decline and fall of blood vessels. Organogenesis 6(1):1–10. https://doi.org/10.4161/org.6.1.10427

    Article  PubMed  PubMed Central  Google Scholar 

  4. Wong BW, Marsch E, Treps L, Baes M, Carmeliet P (2017) Endothelial cell metabolism in health and disease: impact of hypoxia. EMBO J 36(15):2187–2203. https://doi.org/10.15252/embj.201696150

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Singhal AK, Symons JD, Boudina S, Jaishy B, Shiu YT (2010) Role of endothelial cells in myocardial ischemia-reperfusion injury. Vasc Dis Prev 7:1–14. https://doi.org/10.2174/1874120701007010001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Basile DP (2004) Rarefaction of peritubular capillaries following ischemic acute renal failure: a potential factor predisposing to progressive nephropathy. Curr Opin Nephrol Hypertens 13(1):1–7. https://doi.org/10.1097/00041552-200401000-00001

    Article  PubMed  Google Scholar 

  7. Hinkel R, Howe A, Renner S, Ng J, Lee S, Klett K, Kaczmarek V, Moretti A, Laugwitz KL, Skroblin P, Mayr M, Milting H, Dendorfer A, Reichart B, Wolf E, Kupatt C (2017) Diabetes mellitus-induced microvascular destabilization in the myocardium. J Am Coll Cardiol 69(2):131–143. https://doi.org/10.1016/j.jacc.2016.10.058

    Article  CAS  PubMed  Google Scholar 

  8. Yeung L, Wu IW, Sun CC, Liu CF, Chen SY, Tseng CH, Lee HC, Lee CC (2019) Early retinal microvascular abnormalities in patients with chronic kidney disease. Microcirculation. https://doi.org/10.1111/micc.12555

    Article  PubMed  PubMed Central  Google Scholar 

  9. Recio-Mayoral A, Rimoldi OE, Camici PG, Kaski JC (2013) Inflammation and microvascular dysfunction in cardiac syndrome X patients without conventional risk factors for coronary artery disease. JACC Cardiovasc Imaging 6(6):660–667. https://doi.org/10.1016/j.jcmg.2012.12.011

    Article  PubMed  Google Scholar 

  10. Kakuta K, Dohi K, Sato Y, Yamanaka T, Kawamura M, Ogura T, Nakamori S, Fujimoto N, Fujii E, Yamada N, Ito M (2016) Chronic inflammatory disease is an independent risk factor for coronary flow velocity reserve impairment unrelated to the processes of coronary artery calcium deposition. J Am Soc Echocardiogr 29(2):173–180. https://doi.org/10.1016/j.echo.2015.09.001

    Article  PubMed  Google Scholar 

  11. Brevetti G, Giugliano G, Brevetti L, Hiatt WR (2010) Inflammation in peripheral artery disease. Circulation 122(18):1862–1875. https://doi.org/10.1161/CIRCULATIONAHA.109.918417

    Article  PubMed  Google Scholar 

  12. Ruparelia N, Chai JT, Fisher EA, Choudhury RP (2017) Inflammatory processes in cardiovascular disease: a route to targeted therapies. Nat Rev Cardiol 14(3):133–144. https://doi.org/10.1038/nrcardio.2016.185

    Article  CAS  PubMed  Google Scholar 

  13. Martínez-Hervás S, González-Navarro H (2019) Anti-inflammatory therapies for cardiovascular disease: signaling pathways and mechanisms. Rev Esp Cardiol 72(9):767–773. https://doi.org/10.1016/j.rec.2019.03.007

    Article  PubMed  Google Scholar 

  14. Ma J, Chen X (2021) Anti-inflammatory therapy for coronary atherosclerotic heart disease: unanswered questions behind existing successes. Front Cardiovasc Med. https://doi.org/10.3389/fcvm.2020.631398

    Article  PubMed  PubMed Central  Google Scholar 

  15. Ueland T, Aukrust P, Aakhus S, Smith C, Endresen K, Birkeland KI, Gullestad L, Johansen OE (2012) Activin A and cardiovascular disease in type 2 diabetes mellitus. Diab Vasc Dis Res 9(3):234–237. https://doi.org/10.1177/1479164111431171

    Article  PubMed  Google Scholar 

  16. Yndestad A, Ueland T, Oie E, Florholmen G, Halvorsen B, Attramadal H, Simonsen S, Froland SS, Gullestad L, Christensen G, Damas JK, Aukrust P (2004) Elevated levels of activin A in heart failure: potential role in myocardial remodeling. Circulation 109(11):1379–1385. https://doi.org/10.1161/01.CIR.0000120704.97934.41

    Article  CAS  PubMed  Google Scholar 

  17. Miyoshi T, Hirohata S, Uesugi T, Hirota M, Ohnishi H, Nogami K, Hatanaka K, Ogawa H, Usui S, Kusachi S (2009) Relationship between activin A level and infarct size in patients with acute myocardial infarction undergoing successful primary coronary intervention. Clin Chim Acta 401(1–2):3–7. https://doi.org/10.1016/j.cca.2008.10.027

    Article  CAS  PubMed  Google Scholar 

  18. Jones KL, Brauman JN, Groome NP, de Kretser DM, Phillips DJ (2000) Activin A release into the circulation is an early event in systemic inflammation and precedes the release of follistatin. Endocrinology 141(5):1905–1908. https://doi.org/10.1210/endo.141.5.7531

    Article  CAS  PubMed  Google Scholar 

  19. Takahashi S, Nakasatomi M, Takei Y, Ikeuchi H, Sakairi T, Kaneko Y, Hiromura K, Nojima Y, Maeshima A (2018) Identification of urinary activin A as a novel biomarker reflecting the severity of acute kidney injury. Sci Rep 8(1):5176. https://doi.org/10.1038/s41598-018-23564-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Zou L, Liu J, Lu H (2018) Correlation of concentrations of activin A with occurrence and severity of knee osteoarthritis. J Musculoskelet Neuronal Interact 18(3):320–322

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Zhou G, Gui X, Chen R, Fu X, Ji X, Ding H (2019) Elevated serum Activin A in chronic obstructive pulmonary disease with skeletal muscle wasting. Clinics. https://doi.org/10.6061/clinics/2019/e981

    Article  PubMed  PubMed Central  Google Scholar 

  22. Lin JF, Hsu SY, Teng MS, Wu S, Hsieh CA, Jang SJ, Liu CJ, Huang HL, Ko YL (2016) Activin A predicts left ventricular remodeling and mortality in patients with ST-elevation myocardial infarction. Acta Cardiol Sin 32(4):420–427. https://doi.org/10.6515/acs20150415a

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Wei Q, Wang YN, Liu HY, Yang J, Yang CY, Liu M, Liu YF, Yang P, Liu ZH (2013) The expression and role of activin A and follistatin in heart failure rats after myocardial infarction. Int J Cardiol 168(3):2994–2997. https://doi.org/10.1016/j.ijcard.2013.04.012

    Article  PubMed  Google Scholar 

  24. Chen WJ, Greulich S, van der Meer RW, Rijzewijk LJ, Lamb HJ, de Roos A, Smit JW, Romijn JA, Ruige JB, Lammertsma AA, Lubberink M, Diamant M, Ouwens DM (2013) Activin A is associated with impaired myocardial glucose metabolism and left ventricular remodeling in patients with uncomplicated type 2 diabetes. Cardiovasc Diabetol 12:150. https://doi.org/10.1186/1475-2840-12-150

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Fukushima N, Matsuura K, Akazawa H, Honda A, Nagai T, Takahashi T, Seki A, Murasaki KM, Shimizu T, Okano T, Hagiwara N, Komuro I (2011) A crucial role of activin A-mediated growth hormone suppression in mouse and human heart failure. PLoS ONE 6(12):e27901. https://doi.org/10.1371/journal.pone.0027901

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Masutani S (2019) Activin A- a potentially useful biomarker of diastolic dysfunction. Circ J 83(7):1443–1445. https://doi.org/10.1253/circj.CJ-19-0449

    Article  CAS  PubMed  Google Scholar 

  27. Agapova OA, Fang Y, Sugatani T, Seifert ME, Hruska KA (2016) Ligand trap for the activin type IIA receptor protects against vascular disease and renal fibrosis in mice with chronic kidney disease. Kidney Int 89(6):1231–1243. https://doi.org/10.1016/j.kint.2016.02.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Bian X, Griffin TP, Zhu X, Islam MN, Conley SM, Eirin A, Tang H, O’Shea PM, Palmer AK, McCoy RG, Herrmann SM, Mehta RA, Woollard JR, Rule AD, Kirkland JL, Tchkonia T, Textor SC, Griffin MD, Lerman LO, Hickson LJ (2019) Senescence marker activin A is increased in human diabetic kidney disease: association with kidney function and potential implications for therapy. BMJ Open Diabetes Res Care 7(1):e000720. https://doi.org/10.1136/bmjdrc-2019-000720

    Article  PubMed  PubMed Central  Google Scholar 

  29. Maeshima A, Zhang YQ, Nojima Y, Naruse T, Kojima I (2001) Involvement of the activin-follistatin system in tubular regeneration after renal ischemia in rats. J Am Soc Nephrol 12(8):1685–1695

    Article  CAS  PubMed  Google Scholar 

  30. Muttukrishna S, Knight PG, Groome NP, Redman CW, Ledger WL (1997) Activin A and inhibin A as possible endocrine markers for pre-eclampsia. Lancet 349(9061):1285–1288. https://doi.org/10.1016/s0140-6736(96)09264-1

    Article  CAS  PubMed  Google Scholar 

  31. Su X, Huang L, Xiao D, Qu Y, Mu D (2018) Research progress on the role and mechanism of action of Activin A in brain injury. Front Neurosci 12:697. https://doi.org/10.3389/fnins.2018.00697

    Article  PubMed  PubMed Central  Google Scholar 

  32. Florio P, Gazzolo D, Luisi S, Petraglia F (2007) Activin A in brain injury. Adv Clin Chem 43:117–130. https://doi.org/10.1016/s0065-2423(06)43004-3

    Article  CAS  PubMed  Google Scholar 

  33. Leonhard WN, Kunnen SJ, Plugge AJ, Pasternack A, Jianu SBT, Veraar K, el Bouazzaoui F, Hoogaars WMH, ten Dijke P, Breuning MH, De Heer E, Ritvos O, Peters DJM (2016) Inhibition of activin signaling slows progression of polycystic kidney disease. J Am Soc Nephrol 27(12):3589–3599. https://doi.org/10.1681/asn.2015030287

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Maeshima A, Miya M, Mishima K, Yamashita S, Kojima I, Nojima Y (2008) Activin A: autocrine regulator of kidney development and repair. Endocr J 55(1):1–9. https://doi.org/10.1507/endocrj.kr-113

    Article  CAS  PubMed  Google Scholar 

  35. Hedger MP, de Kretser DM (2013) The activins and their binding protein, follistatin-diagnostic and therapeutic targets in inflammatory disease and fibrosis. Cytokine Growth Factor Rev 24(3):285–295. https://doi.org/10.1016/j.cytogfr.2013.03.003

    Article  CAS  PubMed  Google Scholar 

  36. Oshima Y, Ouchi N, Shimano M, Pimentel DR, Papanicolaou KN, Panse KD, Tsuchida K, Lara-Pezzi E, Lee SJ, Walsh K (2009) Activin A and follistatin-like 3 determine the susceptibility of heart to ischemic injury. Circulation 120(16):1606–1615. https://doi.org/10.1161/CIRCULATIONAHA.109.872200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Maeshima K, Maeshima A, Hayashi Y, Kishi S, Kojima I (2004) Crucial role of activin a in tubulogenesis of endothelial cells induced by vascular endothelial growth factor. Endocrinology 145(8):3739–3745. https://doi.org/10.1210/en.2004-0213

    Article  CAS  PubMed  Google Scholar 

  38. Kaneda H, Arao T, Matsumoto K, De Velasco MA, Tamura D, Aomatsu K, Kudo K, Sakai K, Nagai T, Fujita Y, Tanaka K, Yanagihara K, Yamada Y, Okamoto I, Nakagawa K, Nishio K (2011) Activin A inhibits vascular endothelial cell growth and suppresses tumour angiogenesis in gastric cancer. Br J Cancer 105(8):1210–1217. https://doi.org/10.1038/bjc.2011.348

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Poulaki V, Mitsiades N, Kruse FE, Radetzky S, Iliaki E, Kirchhof B, Joussen AM (2004) Activin a in the regulation of corneal neovascularization and vascular endothelial growth factor expression. Am J Pathol 164(4):1293–1302. https://doi.org/10.1016/S0002-9440(10)63216-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Ervolino De Oliveira C, Dourado MR, Sawazaki-Calone I, Costa De Medeiros M, Rossa Junior C, De Karla CN, Esquiche Leon J, Lambert D, Salo T, Graner E, Coletta RD (2020) Activin A triggers angiogenesis via regulation of VEGFA and its overexpression is associated with poor prognosis of oral squamous cell carcinoma. Int J Oncol 57(1):364–376. https://doi.org/10.3892/ijo.2020.5058

    Article  CAS  PubMed  Google Scholar 

  41. Hayashi Y, Maeshima K, Goto F, Kojima I (2007) Activin A as a critical mediator of capillary formation: interaction with the fibroblast growth factor action. Endocr J 54(2):311–318. https://doi.org/10.1507/endocrj.k06-222

    Article  CAS  PubMed  Google Scholar 

  42. Samitas K, Poulos N, Semitekolou M, Morianos I, Tousa S, Economidou E, Robinson DS, Kariyawasam HH, Zervas E, Corrigan CJ, Ying S, Xanthou G, Gaga M (2016) Activin-A is overexpressed in severe asthma and is implicated in angiogenic processes. Eur Respir J 47(3):769–782. https://doi.org/10.1183/13993003.00437-2015

    Article  CAS  PubMed  Google Scholar 

  43. Yang C, Liu J, Liu K, Du B, Shi K, Ding M, Li B, Yang P (2018) Ghrelin suppresses cardiac fibrosis of post-myocardial infarction heart failure rats by adjusting the activin A-follistatin imbalance. Peptides 99:27–35. https://doi.org/10.1016/j.peptides.2017.10.018

    Article  CAS  PubMed  Google Scholar 

  44. Verhamme FM, Bracke KR, Amatngalim GD, Verleden GM, Van Pottelberge GR, Hiemstra PS, Joos GF, Brusselle GG (2014) Role of activin-A in cigarette smoke-induced inflammation and COPD. Eur Respir J 43(4):1028–1041. https://doi.org/10.1183/09031936.00082413

    Article  CAS  PubMed  Google Scholar 

  45. Jones KL, Mansell A, Patella S, Scott BJ, Hedger MP, de Kretser DM, Phillips DJ (2007) Activin A is a critical component of the inflammatory response, and its binding protein, follistatin, reduces mortality in endotoxemia. Proc Natl Acad Sci U S A 104(41):16239–16244. https://doi.org/10.1073/pnas.0705971104

    Article  PubMed  PubMed Central  Google Scholar 

  46. Traktuev DO, Merfeld-Clauss S, Li J, Kolonin M, Arap W, Pasqualini R, Johnstone BH, March KL (2008) A population of multipotent CD34-positive adipose stromal cells share pericyte and mesenchymal surface markers, reside in a periendothelial location, and stabilize endothelial networks. Circ Res 102(1):77–85. https://doi.org/10.1161/CIRCRESAHA.107.159475

    Article  CAS  PubMed  Google Scholar 

  47. Ingram DA, Mead LE, Tanaka H, Meade V, Fenoglio A, Mortell K, Pollok K, Ferkowicz MJ, Gilley D, Yoder MC (2004) Identification of a novel hierarchy of endothelial progenitor cells using human peripheral and umbilical cord blood. Blood 104(9):2752–2760. https://doi.org/10.1182/blood-2004-04-1396

    Article  CAS  PubMed  Google Scholar 

  48. Ngkelo A, Meja K, Yeadon M, Adcock I, Kirkham PA (2012) LPS induced inflammatory responses in human peripheral blood mononuclear cells is mediated through NOX4 and Gialpha dependent PI-3kinase signalling. J Inflamm 9(1):1. https://doi.org/10.1186/1476-9255-9-1

    Article  CAS  Google Scholar 

  49. Merfeld-Clauss S, Gollahalli N, March KL, Traktuev DO (2010) Adipose tissue progenitor cells directly interact with endothelial cells to induce vascular network formation. Tissue Eng Part A 16(9):2953–2966. https://doi.org/10.1089/ten.TEA.2009.0635

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Golia E, Limongelli G, Natale F, Fimiani F, Maddaloni V, Pariggiano I, Bianchi R, Crisci M, D’Acierno L, Giordano R, Di Palma G, Conte M, Golino P, Russo MG, Calabro R, Calabro P (2014) Inflammation and cardiovascular disease: from pathogenesis to therapeutic target. Curr Atheroscler Rep 16(9):435. https://doi.org/10.1007/s11883-014-0435-z

    Article  CAS  PubMed  Google Scholar 

  51. Koller GM, Schafer C, Kemp SS, Aguera KN, Lin PK, Forgy JC, Griffin CT, Davis GE (2020) Proinflammatory mediators, IL (interleukin)-1β, TNF (tumor necrosis factor) α, and thrombin directly induce capillary tube regression. Arterioscler Thromb Vasc Biol 40(2):365–377. https://doi.org/10.1161/atvbaha.119.313536

    Article  CAS  PubMed  Google Scholar 

  52. Seeley JJ, Ghosh S (2017) Molecular mechanisms of innate memory and tolerance to LPS. J Leukoc Biol 101(1):107–119. https://doi.org/10.1189/jlb.3MR0316-118RR

    Article  CAS  PubMed  Google Scholar 

  53. Jansky L, Reymanova P, Kopecky J (2003) Dynamics of cytokine production in human peripheral blood mononuclear cells stimulated by LPS or infected by Borrelia. Physiol Res 52(6):593–598

    PubMed  Google Scholar 

  54. Merfeld-Clauss S, Lu H, Wu X, March KL, Traktuev DO (2018) Hypoxia-induced activin A diminishes endothelial cell vasculogenic activity. J Cell Mol Med 22(1):173–184. https://doi.org/10.1111/jcmm.13306

    Article  CAS  PubMed  Google Scholar 

  55. Takahashi S, Uchimaru K, Harigaya K, Asano S, Yamashita T (1992) Tumor necrosis factor and interleukin-1 induce activin A gene expression in a human bone marrow stromal cell line. Biochem Biophys Res Commun 188(1):310–317. https://doi.org/10.1016/0006-291x(92)92386-c

    Article  CAS  PubMed  Google Scholar 

  56. Arai KY, Ono M, Kudo C, Fujioka A, Okamura R, Nomura Y, Nishiyama T (2011) IL-1beta stimulates activin betaA mRNA expression in human skin fibroblasts through the MAPK pathways, the nuclear factor-kappaB pathway, and prostaglandin E2. Endocrinology 152(10):3779–3790. https://doi.org/10.1210/en.2011-0255

    Article  CAS  PubMed  Google Scholar 

  57. Florio P, Rossi M, Viganò P, Luisi S, Torricelli M, Torres PB, Di Blasio AM, Petraglia F (2007) Interleukin 1beta and progesterone stimulate activin a expression and secretion from cultured human endometrial stromal cells. Reprod Sci 14(1):29–36. https://doi.org/10.1177/1933719106298191

    Article  CAS  PubMed  Google Scholar 

  58. Abe M, Shintani Y, Eto Y, Harada K, Fujinaka Y, Kosaka M, Matsumoto T (2001) Interleukin-1 beta enhances and interferon-gamma suppresses activin A actions by reciprocally regulating activin A and follistatin secretion from bone marrow stromal fibroblasts. Clin Exp Immunol 126(1):64–68. https://doi.org/10.1046/j.1365-2249.2001.01644.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Merfeld-Clauss S, Lupov IP, Lu H, March KL, Traktuev DO (2015) Adipose stromal cell contact with endothelial cells results in loss of complementary vasculogenic activity mediated by induction of Activin A. Stem Cells. https://doi.org/10.1002/stem.2074

    Article  PubMed  Google Scholar 

  60. 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. J Clin Invest 100(3):639–648. https://doi.org/10.1172/jci119575

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Carmeliet P (2000) Mechanisms of angiogenesis and arteriogenesis. Nat Med 6(4):389–395. https://doi.org/10.1038/74651

    Article  CAS  PubMed  Google Scholar 

  62. Bergers G, Javaherian K, Lo KM, Folkman J, Hanahan D (1999) Effects of angiogenesis inhibitors on multistage carcinogenesis in mice. Science 284(5415):808–812. https://doi.org/10.1126/science.284.5415.808

    Article  CAS  PubMed  Google Scholar 

  63. Merfeld-Clauss S, Lease BR, Lu H, March KL, Traktuev DO (2017) Adipose stromal cells differentiation toward smooth muscle cell phenotype diminishes their vasculogenic activity due to induction of activin A secretion. J Tissue Eng Regen Med 11(11):3145–3156. https://doi.org/10.1002/term.2223

    Article  CAS  PubMed  Google Scholar 

  64. Chung ES, Packer M, Lo KH, Fasanmade AA, Willerson JT (2003) Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-alpha, in patients with moderate-to-severe heart failure: results of the anti-TNF therapy against congestive heart failure (ATTACH) trial. Circulation 107(25):3133–3140. https://doi.org/10.1161/01.Cir.0000077913.60364.D2

    Article  CAS  PubMed  Google Scholar 

  65. Yung LM, Yang P, Joshi S, Augur ZM, Kim SSJ, Bocobo GA, Dinter T, Troncone L, Chen PS, McNeil ME, Southwood M, Poli de Frias S, Knopf J, Rosas IO, Sako D, Pearsall RS, Quisel JD, Li G, Kumar R, Yu PB (2020) ACTRIIA-Fc rebalances activin/GDF versus BMP signaling in pulmonary hypertension. Sci Transl Med. https://doi.org/10.1126/scitranslmed.aaz5660

    Article  PubMed  PubMed Central  Google Scholar 

  66. Lotinun S, Pearsall RS, Horne WC, Baron R (2012) Activin receptor signaling: a potential therapeutic target for osteoporosis. Curr Mol Pharmacol 5(2):195–204. https://doi.org/10.2174/1874467211205020195

    Article  CAS  PubMed  Google Scholar 

  67. Pistilli EE, Bogdanovich S, Goncalves MD, Ahima RS, Lachey J, Seehra J, Khurana T (2011) Targeting the activin type IIB receptor to improve muscle mass and function in the mdx mouse model of Duchenne muscular dystrophy. Am J Pathol 178(3):1287–1297. https://doi.org/10.1016/j.ajpath.2010.11.071

    Article  PubMed  PubMed Central  Google Scholar 

  68. Hatsell SJ, Idone V, Wolken DM, Huang L, Kim HJ, Wang L, Wen X, Nannuru KC, Jimenez J, Xie L, Das N, Makhoul G, Chernomorsky R, Ambrosio D, Corpina RA, Schoenherr CJ, Feeley K, Yu PB, Yancopoulos GD, Murphy AJ, Economides AN (2015) ACVR1R206H receptor mutation causes fibrodysplasia ossificans progressiva by imparting responsiveness to activin A. Sci Transl Med 7(303):303ra137. https://doi.org/10.1126/scitranslmed.aac4358

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Zhou X, Wang JL, Lu J, Song Y, Kwak KS, Jiao Q, Rosenfeld R, Chen Q, Boone T, Simonet WS, Lacey DL, Goldberg AL, Han HQ (2010) Reversal of cancer cachexia and muscle wasting by ActRIIB antagonism leads to prolonged survival. Cell 142(4):531–543. https://doi.org/10.1016/j.cell.2010.07.011

    Article  CAS  PubMed  Google Scholar 

  70. Sarlon G, Zemani F, David L, Duong Van Huyen JP, Dizier B, Grelac F, Colliec-Jouault S, Galy-Fauroux I, Bruneval P, Fischer AM, Emmerich J, Boisson-Vidal C (2012) Therapeutic effect of fucoidan-stimulated endothelial colony-forming cells in peripheral ischemia. J Thromb Haemost 10(1):38–48. https://doi.org/10.1111/j.1538-7836.2011.04554.x

    Article  CAS  PubMed  Google Scholar 

  71. Mena HA, Zubiry PR, Dizier B, Schattner M, Boisson-Vidal C, Negrotto S (2018) Acidic preconditioning of endothelial colony-forming cells (ECFC) promote vasculogenesis under proinflammatory and high glucose conditions in vitro and in vivo. Stem Cell Res Ther 9(1):120. https://doi.org/10.1186/s13287-018-0872-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We would like to thank Drs. Anjelica Gonzalez and Catherine Kim (Yale University) for providing human placental pericytes, as well as Dr. Erika Moore and Holly Ryan (University of Florida) for providing human brain pericytes.

Funding

This research was funded by Gatorade Foundation.

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Authors and Affiliations

  1. UF Center for Regenerative Medicine, Division of Cardiovascular Medicine, Department of Medicine, UF College of Medicine, University of Florida, 1600 SW Archer Road, PO Box 100277, Gainesville, FL, 32610, USA

    Sahana Manohar-Sindhu, Stephanie Merfeld-Clauss, Yana Goddard, Keith L. March & Dmitry O. Traktuev

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  1. Sahana Manohar-Sindhu
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  2. Stephanie Merfeld-Clauss
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  3. Yana Goddard
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  4. Keith L. March
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  5. Dmitry O. Traktuev
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Contributions

SMS and SMC: Conception and design, Collection and/or assembly of data, Data analysis and interpretation, Manuscript writing YG: Collection and/or assembly of data KLM: Data interpretation, Financial support DOT: Conception and design, Collection and/or assembly of data, Data analysis and interpretation, Financial support, Manuscript writing, Final approval of manuscript.

Corresponding author

Correspondence to Dmitry O. Traktuev.

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Competing interests

The authors have no competing interests to declare.

Ethical approval

All procedures involving human participants were approved by the University of Florida Institutional Review Board (IRB201802558, IRB201800081). The study procedures involving animals were approved by the University of Florida Institutional Animal Care and Use Committee (Study# 202110176).

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Informed consent was obtained from all individual participants in the study.

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Manohar-Sindhu, S., Merfeld-Clauss, S., Goddard, Y. et al. Diminished vasculogenesis under inflammatory conditions is mediated by Activin A. Angiogenesis 26, 423–436 (2023). https://doi.org/10.1007/s10456-023-09873-w

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  • DOI: https://doi.org/10.1007/s10456-023-09873-w

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