Skip to main content
SpringerLink
Log in

Protein disulfide isomerase A1 as a novel redox sensor in VEGFR2 signaling and angiogenesis

  • Original Paper
  • Published:
Angiogenesis Aims and scope Submit manuscript

Abstract

VEGFR2 signaling in endothelial cells (ECs) is regulated by reactive oxygen species (ROS) derived from NADPH oxidases (NOXs) and mitochondria, which plays an important role in postnatal angiogenesis. However, it remains unclear how highly diffusible ROS signal enhances VEGFR2 signaling and reparative angiogenesis. Protein disulfide isomerase A1 (PDIA1) functions as an oxidoreductase depending on the redox environment. We hypothesized that PDIA1 functions as a redox sensor to enhance angiogenesis. Here we showed that PDIA1 co-immunoprecipitated with VEGFR2 or colocalized with either VEGFR2 or an early endosome marker Rab5 at the perinuclear region upon stimulation of human ECs with VEGF. PDIA1 silencing significantly reduced VEGF-induced EC migration, proliferation and spheroid sprouting via inhibiting VEGFR2 signaling. Mechanistically, VEGF stimulation rapidly increased Cys-OH formation of PDIA1 via the NOX4–mitochondrial ROS axis. Overexpression of “redox-dead” mutant PDIA1 with replacement of the active four Cys residues with Ser significantly inhibited VEGF-induced PDIA1–CysOH formation and angiogenic responses via reducing VEGFR2 phosphorylation. Pdia1+/− mice showed impaired angiogenesis in developmental retina and Matrigel plug models as well as ex vivo aortic ring sprouting model. Study using hindlimb ischemia model revealed that PDIA1 expression was markedly increased in angiogenic ECs of ischemic muscles, and that ischemia-induced limb perfusion recovery and neovascularization were impaired in EC-specific Pdia1 conditional knockout mice. These results suggest that PDIA1 can sense VEGF-induced H2O2 signal via CysOH formation to promote VEGFR2 signaling and angiogenesis in ECs, thereby enhancing postnatal angiogenesis. The oxidized PDIA1 is a potential therapeutic target for treatment of ischemic vascular diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

Data availability

The authors declare that all supporting data are available within the article (and its data supplement).

References

  1. Ushio-Fukai M (2006) Redox signaling in angiogenesis: role of NADPH oxidase. Cardiovasc Res 71(2):226–235. https://doi.org/10.1016/j.cardiores.2006.04.015

    Article  CAS  Google Scholar 

  2. Ushio-Fukai M (2007) VEGF signaling through NADPH oxidase-derived ROS. Antioxid Redox Signal 9(6):731–739. https://doi.org/10.1089/ars.2007.1556

    Article  CAS  Google Scholar 

  3. Ushio-Fukai M, Urao N (2009) Novel role of NADPH oxidase in angiogenesis and stem/progenitor cell function. Antioxid Redox Signal 11(10):2517–2533. https://doi.org/10.1089/ARS.2009.2582

    Article  CAS  Google Scholar 

  4. Fukai T, Ushio-Fukai M (2011) Superoxide dismutases: role in redox signaling, vascular function, and diseases. Antioxid Redox Signal 15(6):1583–1606. https://doi.org/10.1089/ars.2011.3999

    Article  CAS  Google Scholar 

  5. Lee SR, Kwon KS, Kim SR, Rhee SG (1998) Reversible inactivation of protein-tyrosine phosphatase 1B in A431 cells stimulated with epidermal growth factor. J Biol Chem 273(25):15366–15372. https://doi.org/10.1074/jbc.273.25.15366

    Article  CAS  Google Scholar 

  6. Simons M (2012) An inside view: VEGF receptor trafficking and signaling. Physiology (Bethesda) 27(4):213–222. https://doi.org/10.1152/physiol.00016.2012

    Article  CAS  Google Scholar 

  7. Eichmann A, Simons M (2012) VEGF signaling inside vascular endothelial cells and beyond. Curr Opin Cell Biol 24(2):188–193. https://doi.org/10.1016/j.ceb.2012.02.002

    Article  CAS  Google Scholar 

  8. Fukai T, Ushio-Fukai M (2020) Cross-talk between NADPH oxidase and mitochondria: role in ROS signaling and angiogenesis. Cells. https://doi.org/10.3390/cells9081849

    Article  Google Scholar 

  9. Kim YM, Kim SJ, Tatsunami R, Yamamura H, Fukai T, Ushio-Fukai M (2017) ROS-induced ROS release orchestrated by Nox4, Nox2, and mitochondria in VEGF signaling and angiogenesis. Am J Physiol Cell Physiol 312(6):C749–C764. https://doi.org/10.1152/ajpcell.00346.2016

    Article  Google Scholar 

  10. Poole LB, Karplus PA, Claiborne A (2004) Protein sulfenic acids in redox signaling. Annu Rev Pharmacol Toxicol 44:325–347. https://doi.org/10.1146/annurev.pharmtox.44.101802.121735

    Article  CAS  Google Scholar 

  11. Ushio-Fukai M (2006) Localizing NADPH oxidase-derived ROS. Sci STKE. https://doi.org/10.1126/stke.3492006re8

    Article  Google Scholar 

  12. Charles RL, Schroder E, May G, Free P, Gaffney PR, Wait R, Begum S, Heads RJ, Eaton P (2007) Protein sulfenation as a redox sensor: proteomics studies using a novel biotinylated dimedone analogue. Mol Cell Proteomics 6(9):1473–1484. https://doi.org/10.1074/mcp.M700065-MCP200

    Article  CAS  Google Scholar 

  13. Poole LB, Nelson KJ (2008) Discovering mechanisms of signaling-mediated cysteine oxidation. Curr Opin Chem Biol 12(1):18–24. https://doi.org/10.1016/j.cbpa.2008.01.021

    Article  CAS  Google Scholar 

  14. Benham AM (2012) The protein disulfide isomerase family: key players in health and disease. Antioxid Redox Signal 16(8):781–789. https://doi.org/10.1089/ars.2011.4439

    Article  CAS  Google Scholar 

  15. Laurindo FR, Pescatore LA, Fernandes Dde C (2012) Protein disulfide isomerase in redox cell signaling and homeostasis. Free Radical Biol Med 52(9):1954–1969. https://doi.org/10.1016/j.freeradbiomed.2012.02.037

    Article  CAS  Google Scholar 

  16. Cremers CM, Jakob U (2013) Oxidant sensing by reversible disulfide bond formation. J Biol Chem 288(37):26489–26496. https://doi.org/10.1074/jbc.R113.462929

    Article  CAS  Google Scholar 

  17. Xiong B, Jha V, Min JK, Cho J (2020) Protein disulfide isomerase in cardiovascular disease. Exp Mol Med 52(3):390–399. https://doi.org/10.1038/s12276-020-0401-5

    Article  CAS  Google Scholar 

  18. Kim YM, Youn SW, Sudhahar V, Das A, Chandhri R, Cuervo Grajal H, Kweon J, Leanhart S, He L, Toth PT, Kitajewski J, Rehman J, Yoon Y, Cho J, Fukai T, Ushio-Fukai M (2018) Redox regulation of mitochondrial fission protein Drp1 by protein disulfide isomerase limits endothelial senescence. Cell Rep 23(12):3565–3578. https://doi.org/10.1016/j.celrep.2018.05.054

    Article  CAS  Google Scholar 

  19. Laurindo FR, Fernandes DC, Amanso AM, Lopes LR, Santos CX (2008) Novel role of protein disulfide isomerase in the regulation of NADPH oxidase activity: pathophysiological implications in vascular diseases. Antioxid Redox Signal 10(6):1101–1113. https://doi.org/10.1089/ars.2007.2011

    Article  CAS  Google Scholar 

  20. Hahm E, Li J, Kim K, Huh S, Rogelj S, Cho J (2013) Extracellular protein disulfide isomerase regulates ligand-binding activity of alphaMbeta2 integrin and neutrophil recruitment during vascular inflammation. Blood 121(19):3789–3800. https://doi.org/10.1182/blood-2012-11-467985

    Article  CAS  Google Scholar 

  21. Zhou J, Wu Y, Wang L, Rauova L, Hayes VM, Poncz M, Essex DW (2015) The C-terminal CGHC motif of protein disulfide isomerase supports thrombosis. J Clin Invest 125(12):4391–4406. https://doi.org/10.1172/JCI80319

    Article  Google Scholar 

  22. Chen MJ, Yokomizo T, Zeigler BM, Dzierzak E, Speck NA (2009) Runx1 is required for the endothelial to haematopoietic cell transition but not thereafter. Nature 457(7231):887–891. https://doi.org/10.1038/nature07619

    Article  CAS  Google Scholar 

  23. Baker M, Robinson SD, Lechertier T, Barber PR, Tavora B, D’Amico G, Jones DT, Vojnovic B, Hodivala-Dilke K (2011) Use of the mouse aortic ring assay to study angiogenesis. Nat Protoc 7(1):89–104. https://doi.org/10.1038/nprot.2011.435

    Article  CAS  Google Scholar 

  24. Chen GF, Sudhahar V, Youn SW, Das A, Cho J, Kamiya T, Urao N, McKinney RD, Surenkhuu B, Hamakubo T, Iwanari H, Li S, Christman JW, Shantikumar S, Angelini GD, Emanueli C, Ushio-Fukai M, Fukai T (2015) Copper transport protein antioxidant-1 promotes inflammatory neovascularization via chaperone and transcription factor function. Sci Rep 5:14780. https://doi.org/10.1038/srep14780

    Article  CAS  Google Scholar 

  25. Tojo T, Ushio-Fukai M, Yamaoka-Tojo M, Ikeda S, Patrushev N, Alexander RW (2005) Role of gp91phox (Nox2)-containing NAD(P)H oxidase in angiogenesis in response to hindlimb ischemia. Circulation 111(18):2347–2355. https://doi.org/10.1161/01.CIR.0000164261.62586.14

    Article  CAS  Google Scholar 

  26. Urao N, Sudhahar V, Kim SJ, Chen GF, McKinney RD, Kojda G, Fukai T, Ushio-Fukai M (2013) Critical role of endothelial hydrogen peroxide in post-ischemic neovascularization. PLoS ONE 8(3):e57618. https://doi.org/10.1371/journal.pone.0057618

    Article  CAS  Google Scholar 

  27. Das A, Sudhahar V, Chen GF, Kim HW, Youn SW, Finney L, Vogt S, Yang J, Kweon J, Surenkhuu B, Ushio-Fukai M, Fukai T (2016) Endothelial antioxidant-1: a key mediator of copper-dependent wound healing in vivo. Sci Rep 6:33783. https://doi.org/10.1038/srep33783

    Article  CAS  Google Scholar 

  28. Chabot S, Jabrane-Ferrat N, Bigot K, Tabiasco J, Provost A, Golzio M, Noman MZ, Giustiniani J, Bellard E, Brayer S, Aguerre-Girr M, Meggetto F, Giuriato S, Malecaze F, Galiacy S, Jais JP, Chose O, Kadouche J, Chouaib S, Teissie J, Abitbol M, Bensussan A, Le Bouteiller P (2011) A novel antiangiogenic and vascular normalization therapy targeted against human CD160 receptor. J Exp Med 208(5):973–986. https://doi.org/10.1084/jem.20100810

    Article  CAS  Google Scholar 

  29. Oshikawa J, Kim SJ, Furuta E, Caliceti C, Chen GF, McKinney RD, Kuhr F, Levitan I, Fukai T, Ushio-Fukai M (2012) Novel role of p66Shc in ROS-dependent VEGF signaling and angiogenesis in endothelial cells. Am J Physiol Heart Circ Physiol 302(3):H724-732. https://doi.org/10.1152/ajpheart.00739.2011

    Article  CAS  Google Scholar 

  30. Oshikawa J, Urao N, Kim HW, Kaplan N, Razvi M, McKinney R, Poole LB, Fukai T, Ushio-Fukai M (2010) Extracellular SOD-derived H2O2 promotes VEGF signaling in caveolae/lipid rafts and post-ischemic angiogenesis in mice. PLoS ONE 5(4):e10189. https://doi.org/10.1371/journal.pone.0010189

    Article  CAS  Google Scholar 

  31. Wang S, Amato KR, Song W, Youngblood V, Lee K, Boothby M, Brantley-Sieders DM, Chen J (2015) Regulation of endothelial cell proliferation and vascular assembly through distinct mTORC2 signaling pathways. Mol Cell Biol 35(7):1299–1313. https://doi.org/10.1128/MCB.00306-14

    Article  CAS  Google Scholar 

  32. Ash D, Sudhahar V, Youn SW, Okur MN, Das A, O’Bryan JP, McMenamin M, Hou Y, Kaplan JH, Fukai T, Ushio-Fukai M (2021) The P-type ATPase transporter ATP7A promotes angiogenesis by limiting autophagic degradation of VEGFR2. Nat Commun 12(1):3091. https://doi.org/10.1038/s41467-021-23408-1

    Article  CAS  Google Scholar 

  33. Urao N, Inomata H, Razvi M, Kim HW, Wary K, McKinney R, Fukai T, Ushio-Fukai M (2008) Role of nox2-based NADPH oxidase in bone marrow and progenitor cell function involved in neovascularization induced by hindlimb ischemia. Circ Res 103(2):212–220. https://doi.org/10.1161/CIRCRESAHA.108.176230

    Article  CAS  Google Scholar 

  34. Simons M, Gordon E, Claesson-Welsh L (2016) Mechanisms and regulation of endothelial VEGF receptor signalling. Nat Rev Mol Cell Biol 17(10):611–625. https://doi.org/10.1038/nrm.2016.87

    Article  CAS  Google Scholar 

  35. Freedman RB, Gane PJ, Hawkins HC, Hlodan R, McLaughlin SH, Parry JW (1998) Experimental and theoretical analyses of the domain architecture of mammalian protein disulphide-isomerase. Biol Chem 379(3):321–328. https://doi.org/10.1515/bchm.1998.379.3.321

    Article  CAS  Google Scholar 

  36. Alanen HI, Salo KE, Pekkala M, Siekkinen HM, Pirneskoski A, Ruddock LW (2003) Defining the domain boundaries of the human protein disulfide isomerases. Antioxid Redox Signal 5(4):367–374. https://doi.org/10.1089/152308603768295096

    Article  CAS  Google Scholar 

  37. Nakamura Y, Patrushev N, Inomata H, Mehta D, Urao N, Kim HW, Razvi M, Kini V, Mahadev K, Goldstein BJ, McKinney R, Fukai T, Ushio-Fukai M (2008) Role of protein tyrosine phosphatase 1B in vascular endothelial growth factor signaling and cell-cell adhesions in endothelial cells. Circ Res 102(10):1182–1191. https://doi.org/10.1161/CIRCRESAHA.107.167080

    Article  CAS  Google Scholar 

  38. Lanahan AA, Lech D, Dubrac A, Zhang J, Zhuang ZW, Eichmann A, Simons M (2014) PTP1b is a physiologic regulator of vascular endothelial growth factor signaling in endothelial cells. Circulation 130(11):902–909. https://doi.org/10.1161/CIRCULATIONAHA.114.009683

    Article  CAS  Google Scholar 

  39. Salmeen A, Andersen JN, Myers MP, Meng TC, Hinks JA, Tonks NK, Barford D (2003) Redox regulation of protein tyrosine phosphatase 1B involves a sulphenyl-amide intermediate. Nature 423(6941):769–773. https://doi.org/10.1038/nature01680

    Article  CAS  Google Scholar 

  40. Londhe AD, Bergeron A, Curley SM, Zhang F, Rivera KD, Kannan A, Coulis G, Rizvi SHM, Kim SJ, Pappin DJ, Tonks NK, Linhardt RJ, Boivin B (2020) Regulation of PTP1B activation through disruption of redox-complex formation. Nat Chem Biol 16(2):122–125. https://doi.org/10.1038/s41589-019-0433-0

    Article  CAS  Google Scholar 

  41. Tian F, Zhou X, Wikstrom J, Karlsson H, Sjoland H, Gan LM, Boren J, Akyurek LM (2009) Protein disulfide isomerase increases in myocardial endothelial cells in mice exposed to chronic hypoxia: a stimulatory role in angiogenesis. Am J Physiol Heart Circ Physiol 297(3):H1078-1086. https://doi.org/10.1152/ajpheart.00937.2008

    Article  CAS  Google Scholar 

  42. Li J, Kim K, Jeong SY, Chiu J, Xiong B, Petukhov PA, Dai X, Li X, Andrews RK, Du X, Hogg PJ, Cho J (2019) Platelet protein disulfide isomerase promotes glycoprotein ibalpha-mediated platelet-neutrophil interactions under thromboinflammatory conditions. Circulation 139(10):1300–1319. https://doi.org/10.1161/CIRCULATIONAHA.118.036323

    Article  CAS  Google Scholar 

  43. Camargo LL, Babelova A, Mieth A, Weigert A, Mooz J, Rajalingam K, Heide H, Wittig I, Lopes LR, Brandes RP (2013) Endo-PDI is required for TNFalpha-induced angiogenesis. Free Radical Biol Med 65:1398–1407. https://doi.org/10.1016/j.freeradbiomed.2013.09.028

    Article  CAS  Google Scholar 

  44. Kang DH, Lee DJ, Lee KW, Park YS, Lee JY, Lee SH, Koh YJ, Koh GY, Choi C, Yu DY, Kim J, Kang SW (2011) Peroxiredoxin II is an essential antioxidant enzyme that prevents the oxidative inactivation of VEGF receptor-2 in vascular endothelial cells. Mol Cell 44(4):545–558. https://doi.org/10.1016/j.molcel.2011.08.040

    Article  CAS  Google Scholar 

  45. Kenche H, Ye ZW, Vedagiri K, Richards DM, Gao XH, Tew KD, Townsend DM, Blumental-Perry A (2016) Adverse outcomes associated with cigarette smoke radicals related to damage to protein-disulfide isomerase. J Biol Chem 291(9):4763–4778. https://doi.org/10.1074/jbc.M115.712331

    Article  CAS  Google Scholar 

  46. Townsend DM, Manevich Y, He L, Xiong Y, Bowers RR Jr, Hutchens S, Tew KD (2009) Nitrosative stress-induced s-glutathionylation of protein disulfide isomerase leads to activation of the unfolded protein response. Cancer Res 69(19):7626–7634. https://doi.org/10.1158/0008-5472.CAN-09-0493

    Article  CAS  Google Scholar 

  47. Uehara T, Nakamura T, Yao D, Shi ZQ, Gu Z, Ma Y, Masliah E, Nomura Y, Lipton SA (2006) S-nitrosylated protein-disulphide isomerase links protein misfolding to neurodegeneration. Nature 441(7092):513–517. https://doi.org/10.1038/nature04782

    Article  CAS  Google Scholar 

  48. Wroblewski VJ, Masnyk M, Khambatta SS, Becker GW (1992) Mechanisms involved in degradation of human insulin by cytosolic fractions of human, monkey, and rat liver. Diabetes 41(4):539–547. https://doi.org/10.2337/diab.41.4.539

    Article  CAS  Google Scholar 

  49. Turano C, Coppari S, Altieri F, Ferraro A (2002) Proteins of the PDI family: unpredicted non-ER locations and functions. J Cell Physiol 193(2):154–163. https://doi.org/10.1002/jcp.10172

    Article  CAS  Google Scholar 

  50. Parakh S, Atkin JD (2015) Novel roles for protein disulphide isomerase in disease states: a double edged sword? Front Cell Dev Biol 3:30. https://doi.org/10.3389/fcell.2015.00030

    Article  Google Scholar 

  51. El Hindy M, Hezwani M, Corry D, Hull J, El Amraoui F, Harris M, Lee C, Forshaw T, Wilson A, Mansbridge A, Hassler M, Patel VB, Kehoe PG, Love S, Conway ME (2014) The branched-chain aminotransferase proteins: novel redox chaperones for protein disulfide isomerase–implications in Alzheimer’s disease. Antioxid Redox Signal 20(16):2497–2513. https://doi.org/10.1089/ars.2012.4869

    Article  CAS  Google Scholar 

  52. Soares Moretti AI, Martins Laurindo FR (2017) Protein disulfide isomerases: redox connections in and out of the endoplasmic reticulum. Arch Biochem Biophys 617:106–119. https://doi.org/10.1016/j.abb.2016.11.007

    Article  CAS  Google Scholar 

  53. Raiborg C, Wenzel EM, Stenmark H (2015) ER-endosome contact sites: molecular compositions and functions. EMBO J 34(14):1848–1858. https://doi.org/10.15252/embj.201591481

    Article  CAS  Google Scholar 

  54. Aoyama-Ishiwatari S, Hirabayashi Y (2021) Endoplasmic reticulum-mitochondria contact sites-emerging intracellular signaling hubs. Front Cell Dev Biol 9:653828. https://doi.org/10.3389/fcell.2021.653828

    Article  Google Scholar 

  55. Boivin B, Yang M, Tonks NK (2010) Targeting the reversibly oxidized protein tyrosine phosphatase superfamily. Sci Signal. https://doi.org/10.1126/scisignal.3137pl2

    Article  Google Scholar 

  56. Frangioni JV, Beahm PH, Shifrin V, Jost CA, Neel BG (1992) The nontransmembrane tyrosine phosphatase PTP-1B localizes to the endoplasmic reticulum via its 35 amino acid C-terminal sequence. Cell 68(3):545–560. https://doi.org/10.1016/0092-8674(92)90190-n

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We would like to thank Dr. Henar Cyuervo Grajal at University of Illinois at Chicago for assisting retinal angiogenesis in initial study.

Funding

This work was supported by National Institute of Health grants: R01HL160014, R01HL135584 (to M.U.-F.), R01HL147550 (to M.U.-F., T.F), R01HL133613, R01HL116976 (to T.F., M.U.-F.), R01HL070187 (to T.F.), R01EY011766, R01EY030500, R21EY032265 (R.B.C.), Veterans Administration Merit Review Award 2I01BX001232 (to T.F.), 101BX001233 (R.B.C.), R01HL118526 (D.W.E.). The VA Career Scientist Award (IK6BX005228) (to R.B.C.). R.B. Caldwell is the recipient of a Research Career Scientist Award from the Department of Veterans Affairs. The contents do not represent the views of the Department of Veterans Affairs or the United States Government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Author information

Author notes

  1. Sheela Nagarkoti, Young-Mee Kim: equally contributed first author.

Authors and Affiliations

  1. Vascular Biology Center, Medical College of Georgia at Augusta University, 1460 Laney-Walker Blvd, Augusta, GA, 30912, USA

    Sheela Nagarkoti, Young-Mee Kim, Dipankar Ash, Archita Das, Seock-Won Youn, Varadarajan Sudhahar, Malgorzata McMenamin, Yali Hou, Harriet Boatwright, Ruth Caldwell, Tohru Fukai & Masuko Ushio-Fukai

  2. Department of Medicine (Cardiology), Medical College of Georgia at Augusta University, Augusta, GA, 30912, USA

    Masuko Ushio-Fukai

  3. Departments of Pharmacology and Toxicology, Medical College of Georgia at Augusta University, Augusta, GA, USA

    Tohru Fukai

  4. Vision Discovery Institute, Medical College of Georgia at Augusta University, Augusta, GA, USA

    Ruth Caldwell

  5. Neuroscience and Regenerative Medicine, Medical College of Georgia at Augusta University, Augusta, GA, USA

    Eric Vitriol & Tracy-Ann Read

  6. Charlie Norwood Veterans Affairs Medical Center, Augusta, GA, 30912, USA

    Varadarajan Sudhahar, Malgorzata McMenamin, Yali Hou, Ruth Caldwell & Tohru Fukai

  7. Department of Medicine (Cardiology), University of Illinois at Chicago, Chicago, IL, USA

    Young-Mee Kim

  8. Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL, USA

    Seock-Won Youn

  9. Center for Cardiovascular Research, University of Illinois at Chicago, Chicago, IL, USA

    Seock-Won Youn

  10. Department of Medicine, Temple University School of Medicine, Philadelphia, PA, USA

    David W. Essex

  11. Division of Hematology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA

    Jaehyung Cho

  12. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA

    Jaehyung Cho

Authors
  1. Sheela Nagarkoti
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Young-Mee Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dipankar Ash
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Archita Das
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Eric Vitriol
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tracy-Ann Read
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Seock-Won Youn
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Varadarajan Sudhahar
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Malgorzata McMenamin
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yali Hou
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Harriet Boatwright
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Ruth Caldwell
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. David W. Essex
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Jaehyung Cho
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Tohru Fukai
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Masuko Ushio-Fukai
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

MU-F, TF, SN, Y-MK, designed the study; SN, Y-MK, DA, VS, SWY, YH, AD, EV, TAR performed experiments. MM, HB, performed mouse genotyping. MU-F, TF, SN and Y-MK, DA, AD, analyzed data. VS, RC, DWE, JC, discussed data and provided inputs and reagents. MU-F, TF, SN, Y-MK, wrote the manuscript. RC, DWE, JC. edited the manuscript. All authors read and approved the final version of the manuscript.

Corresponding author

Correspondence to Masuko Ushio-Fukai.

Ethics declarations

Conflict of interest

The authors declare no competing financial interests.

Ethical approval

The animal protocols used in this study were approved by the institutional Animal Care Committee and institutional Biosafety Committee of University of Illinois at Chicago and Augusta University.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 424 KB)

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nagarkoti, S., Kim, YM., Ash, D. et al. Protein disulfide isomerase A1 as a novel redox sensor in VEGFR2 signaling and angiogenesis. Angiogenesis 26, 77–96 (2023). https://doi.org/10.1007/s10456-022-09852-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10456-022-09852-7

Keywords

Search

Navigation