Skip to main content

Advertisement

Log in

Differential regulation of angiogenic cellular processes and claudin-5 by histamine and VEGF via PI3K-signaling, transcription factor SNAI2 and interleukin-8

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

Abstract

Aims

Histamine and vascular endothelial growth factor A (VEGF) are central regulators in vascular pathologies. Their gene regulation leading to vascular remodeling has remained obscure. In this study, EC regulation mechanisms of histamine and VEGF were compared by RNA sequencing of primary endothelial cells (ECs), functional in vitro assays and in vivo permeability mice model.

Methods and results

By RNA sequencing, similar transcriptional alterations of genes involved in activation of primary ECs, cell proliferation and adhesion were observed between histamine and VEGF. Seventy-six commonly regulated genes were found, representing ~53% of all VEGF-regulated transcripts and ~26% of all histamine-regulated transcripts. Both factors regulated tight junction formation and expression of pro-angiogenic transcription factors (TFs) affecting EC survival, migration and tube formation. Novel claudin-5 upstream regulatory genes were identified. VEGF was demonstrated to regulate expression of SNAI2, whereas pro-angiogenic TFs NR4A1, MYCN and RCAN1 were regulated by both histamine and VEGF. Claudin-5 was shown to be regulated VEGFR2/PI3K-Akt dependently by VEGF and PI3K-Akt independently by histamine. Interleukin-8 was shown to downregulate claudin-5 by histamine. Additionally, SNAI2, NR4A1 and MYCN were shown to mediate EC survival, migration and tube formation and to regulate expression of claudin-5. Further systemic delivery of VEGF and histamine was shown to induce a fast vascular hyperpermeability response in intact vasculature of C57/Bl6 mice followed by regulation of NR4A1 and MYCN.

Conclusions

Our study identifies novel claudin-5 upstream regulatory genes of histamine and VEGF that induce cellular angiogenic processes. Our results increase knowledge of angiogenic EC phenotype and provide novel treatment targets for vascular pathologies.

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

Access this article

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Kumar P, Shen Q, Pivetti CD, Lee ES, Wu MH, Yuan SY (2009) Molecular mechanisms of endothelial hyperpermeability: implications in inflammation. Expert Rev Mol Med 11:e19

    Article  PubMed  PubMed Central  Google Scholar 

  2. Olsson AK, Dimberg A, Kreuger J, Claesson-Welsh L (2006) VEGF receptor signalling—in control of vascular function. Nat Rev Mol Cell Biol 7:359–371

    Article  CAS  PubMed  Google Scholar 

  3. Asai K, Kanazawa H, Kamoi H, Shiraishi S, Hirata K, Yoshikawa J (2003) Increased levels of vascular endothelial growth factor in induced sputum in asthmatic patients. Clin Exp Allergy 33:595–599

    Article  CAS  PubMed  Google Scholar 

  4. Brouillard P, Vikkula M (2003) Vascular malformations: localized defects in vascular morphogenesis. Clin Genet 63:340–351

    Article  CAS  PubMed  Google Scholar 

  5. Abdel-Majid RM, Marshall JS (2004) Prostaglandin E2 induces degranulation-independent production of vascular endothelial growth factor by human mast cells. J Immunol 172:1227–1236

    Article  CAS  PubMed  Google Scholar 

  6. Qin L, Zhao D, Xu J, Ren X, Terwilliger EF, Parangi S, Lawler J, Dvorak HF, Zeng H (2013) The vascular permeabilizing factors histamine and serotonin induce angiogenesis through TR3/Nur77 and subsequently truncate it through thrombospondin-1. Blood 121:2154–2164

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Norrby K (1995) Evidence of a dual role of endogenous histamine in angiogenesis. Int J Exp Pathol 76:87–92

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Zauberman H, Michaelson IC, Bergmann F, Maurice DM (1969) Stimulation of neovascularization of the cornea by biogenic amines. Exp Eye Res 8:77–83

    Article  CAS  PubMed  Google Scholar 

  9. Ghosh AK, Hirasawa N, Ohtsu H, Watanabe T, Ohuchi K (2002) Defective angiogenesis in the inflammatory granulation tissue in histidine decarboxylase-deficient mice but not in mast cell-deficient mice. J Exp Med 195:973–982

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Wang D, Garcia-Bassets I, Benner C, Li W, Su X, Zhou Y, Qiu J, Liu W, Kaikkonen MU, Ohgi KA, Glass CK, Rosenfeld MG, Fu XD (2011) Reprogramming transcription by distinct classes of enhancers functionally defined by eRNA. Nature 474:390–394

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Nieminen T, Toivanen PI, Rintanen N, Heikura T, Jauhiainen S, Airenne KJ, Alitalo K, Marjomaki V, Yla-Herttuala S (2014) The impact of the receptor binding profiles of the vascular endothelial growth factors on their angiogenic features. Biochim Biophys Acta 1840:454–463

    Article  CAS  PubMed  Google Scholar 

  12. Dejana E, Tournier-Lasserve E, Weinstein BM (2009) The control of vascular integrity by endothelial cell junctions: molecular basis and pathological implications. Dev Cell 16:209–221

    Article  CAS  PubMed  Google Scholar 

  13. Gavard J, Gutkind JS (2006) VEGF controls endothelial-cell permeability by promoting the beta-arrestin-dependent endocytosis of VE-cadherin. Nat Cell Biol 8:1223–1234

    Article  CAS  PubMed  Google Scholar 

  14. Escudero-Esparza A, Jiang WG, Martin TA (2012) Claudin-5 is involved in breast cancer cell motility through the N-WASP and ROCK signalling pathways. J Exp Clin Cancer Res 31:43-9966-31-43

    Article  Google Scholar 

  15. Escudero-Esparza A, Jiang WG, Martin TA (2012) Claudin-5 participates in the regulation of endothelial cell motility. Mol Cell Biochem 362:71–85

    Article  CAS  PubMed  Google Scholar 

  16. Taddei A, Giampietro C, Conti A, Orsenigo F, Breviario F, Pirazzoli V, Potente M, Daly C, Dimmeler S, Dejana E (2008) Endothelial adherens junctions control tight junctions by VE-cadherin-mediated upregulation of claudin-5. Nat Cell Biol 10:923–934

    Article  CAS  PubMed  Google Scholar 

  17. Yuan L, Le Bras A, Sacharidou A, Itagaki K, Zhan Y, Kondo M, Carman CV, Davis GE, Aird WC, Oettgen P (2012) ETS-related gene (ERG) controls endothelial cell permeability via transcriptional regulation of the claudin 5 (CLDN5) gene. J Biol Chem 287:6582–6591

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Miao YS, Zhao YY, Zhao LN, Wang P, Liu YH, Ma J, Xue YX (2015) MiR-18a increased the permeability of BTB via RUNX1 mediated down-regulation of ZO-1, occludin and claudin-5. Cell Signal 27:156–167

    Article  CAS  PubMed  Google Scholar 

  19. Martinez-Estrada OM, Culleres A, Soriano FX, Peinado H, Bolos V, Martinez FO, Reina M, Cano A, Fabre M, Vilaro S (2006) The transcription factors Slug and Snail act as repressors of Claudin-1 expression in epithelial cells. Biochem J 394:449–457

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Naran S, Zhang X, Hughes SJ (2009) Inhibition of HGF/MET as therapy for malignancy. Expert Opin Ther Targets 13:569–581

    Article  CAS  PubMed  Google Scholar 

  21. Jennische E, Ekberg S, Matejka GL (1993) Expression of hepatocyte growth factor in growing and regenerating rat skeletal muscle. Am J Physiol 265:C122–C128

    CAS  PubMed  Google Scholar 

  22. Yu H, Huang X, Ma Y, Gao M, Wang O, Gao T, Shen Y, Liu X (2013) Interleukin-8 regulates endothelial permeability by down-regulation of tight junction but not dependent on integrins induced focal adhesions. Int J Biol Sci 9:966–979

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Sobrado M, Ramirez BG, Neria F, Lizasoain I, Arbones ML, Minami T, Redondo JM, Moro MA, Cano E (2012) Regulator of calcineurin 1 (Rcan1) has a protective role in brain ischemia/reperfusion injury. J Neuroinflammation 9:48-2094-9-48

  24. Tiruppathi C, Ahmmed GU, Vogel SM, Malik AB (2006) Ca2+ signaling, TRP channels, and endothelial permeability. Microcirculation 13:693–708

    Article  CAS  PubMed  Google Scholar 

  25. Pei L, Castrillo A, Chen M, Hoffmann A, Tontonoz P (2005) Induction of NR4A orphan nuclear receptor expression in macrophages in response to inflammatory stimuli. J Biol Chem 280:29256–29262

    Article  CAS  PubMed  Google Scholar 

  26. Kang J, Rychahou PG, Ishola TA, Mourot JM, Evers BM, Chung DH (2008) N-myc is a novel regulator of PI3K-mediated VEGF expression in neuroblastoma. Oncogene 27:3999–4007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. You B, Jiang YY, Chen S, Yan G, Sun J (2009) The orphan nuclear receptor Nur77 suppresses endothelial cell activation through induction of IkappaBalpha expression. Circ Res 104:742–749

    Article  CAS  PubMed  Google Scholar 

  28. Wessel F, Winderlich M, Holm M, Frye M, Rivera-Galdos R, Vockel M, Linnepe R, Ipe U, Stadtmann A, Zarbock A, Nottebaum AF, Vestweber D (2014) Leukocyte extravasation and vascular permeability are each controlled in vivo by different tyrosine residues of VE-cadherin. Nat Immunol 15:223–230

    Article  CAS  PubMed  Google Scholar 

  29. Argaw AT, Gurfein BT, Zhang Y, Zameer A, John GR (2009) VEGF-mediated disruption of endothelial CLN-5 promotes blood-brain barrier breakdown. Proc Natl Acad Sci USA 106:1977–1982

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Herr D, Sallmann A, Bekes I, Konrad R, Holzheu I, Kreienberg R, Wulff C (2012) VEGF induces ascites in ovarian cancer patients via increasing peritoneal permeability by downregulation of Claudin 5. Gynecol Oncol 127:210–216

    Article  CAS  PubMed  Google Scholar 

  31. Zeng H, Qin L, Zhao D, Tan X, Manseau EJ, Van Hoang M, Senger DR, Brown LF, Nagy JA, Dvorak HF (2006) Orphan nuclear receptor TR3/Nur77 regulates VEGF-A-induced angiogenesis through its transcriptional activity. J Exp Med 203:719–729

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Baggott RR, Alfranca A, Lopez-Maderuelo D, Mohamed TM, Escolano A, Oller J, Ornes BC, Kurusamy S, Rowther FB, Brown JE, Oceandy D, Cartwright EJ, Wang W, Gomez-Del Arco P, Martinez-Martinez S, Neyses L, Redondo JM, Armesilla AL (2014) Plasma Membrane calcium ATPase isoform 4 inhibits vascular endothelial growth factor-mediated angiogenesis Through interaction with calcineurin. Arterioscler Thromb Vasc Biol 34:2310–2320

    Article  CAS  PubMed  Google Scholar 

  33. Pinato G, Pegoraro S, Visentini M, Ruaro ME, Torre V (2009) Elevation of somatic Ca2+ upregulates genes Nr4a1 and Egr2, but not Bdnf and Arc. Neuroreport 20:869–874

    Article  CAS  PubMed  Google Scholar 

  34. Mellstrom B, Savignac M, Gomez-Villafuertes R, Naranjo JR (2008) Ca2+-operated transcriptional networks: molecular mechanisms and in vivo models. Physiol Rev 88:421–449

    Article  CAS  PubMed  Google Scholar 

  35. Beard RS Jr, Haines RJ, Wu KY, Reynolds JJ, Davis SM, Elliott JE, Malinin NL, Chatterjee V, Cha BJ, Wu MH, Yuan SY (2014) Non-muscle Mlck is required for beta-catenin- and FoxO1-dependent downregulation of Cldn5 in IL-1beta-mediated barrier dysfunction in brain endothelial cells. J Cell Sci 127:1840–1853

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Kondo N, Ogawa M, Wada H, Nishikawa S (2009) Thrombin induces rapid disassembly of claudin-5 from the tight junction of endothelial cells. Exp Cell Res 315:2879–2887

    Article  CAS  PubMed  Google Scholar 

  37. Rissanen TT, Korpisalo P, Markkanen JE, Liimatainen T, Orden MR, Kholova I, de Goede A, Heikura T, Grohn OH, Yla-Herttuala S (2005) Blood flow remodels growing vasculature during vascular endothelial growth factor gene therapy and determines between capillary arterialization and sprouting angiogenesis. Circulation 112:3937–3946

    Article  CAS  PubMed  Google Scholar 

  38. Nagy JA, Benjamin L, Zeng H, Dvorak AM, Dvorak HF (2008) Vascular permeability, vascular hyperpermeability and angiogenesis. Angiogenesis 11:109–119

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Fu BM, Shen S (2004) Acute VEGF effect on solute permeability of mammalian microvessels in vivo. Microvasc Res 68:51–62

    Article  CAS  PubMed  Google Scholar 

  40. Matsunaga Y, Yamazaki Y, Suzuki H, Morita T (2009) VEGF-A and VEGF-F evoke distinct changes in vascular ultrastructure. Biochem Biophys Res Commun 379:872–875

    Article  CAS  PubMed  Google Scholar 

  41. Goddard LM, Iruela-Arispe ML (2013) Cellular and molecular regulation of vascular permeability. Thromb Haemost 109:407–415

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Chipumuro E, Marco E, Christensen CL, Kwiatkowski N, Zhang T, Hatheway CM, Abraham BJ, Sharma B, Yeung C, Altabef A, Perez-Atayde A, Wong KK, Yuan GC, Gray NS, Young RA, George RE (2014) CDK7 inhibition suppresses super-enhancer-linked oncogenic transcription in MYCN-driven cancer. Cell 159:1126–1139

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Wang X, Hayashi S, Umezaki M, Yamamoto T, Kageyama-Yahara N, Kondo T, Kadowaki M (2014) Shikonin, a constituent of Lithospermum erythrorhizon exhibits anti-allergic effects by suppressing orphan nuclear receptor Nr4a family gene expression as a new prototype of calcineurin inhibitors in mast cells. Chem Biol Interact 224C:117–127

    Article  Google Scholar 

Download references

Acknowledgements

This study was supported by Academy of Finland (Project No. 250614), CoE of Cardiovascular and Metabolic Disease, ERC Advanced Grant (AdG09-250050) and CARIM PhD and VENI fellowships of the Netherlands Organization of Scientific Research (016.116.017). The personnel of the Kuopio University Hospital maternity ward are thanked for providing the umbilical cords for HUVEC cell isolation.

Author contributions

JPL (Laakkonen) designed, performed research, wrote the paper and provided materials and reagents for the study. JPL (Lappalainen) performed research and wrote the paper. TLT performed research, optimized 2-photon microscopy experiments and edited the paper. PIT and TN contributed VEGF proteins to the study. SJ performed cell experiments and isolated primary human endothelial cells. MUK performed RNA sequencing and data analysis. JCS and SYH edited the paper and provided materials and reagents for the study.

Disclosure

None.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Johanna P. Laakkonen.

Additional information

Johanna P. Laakkonen and Jari P. Lappalainen have contributed equally to this work.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Laakkonen, J.P., Lappalainen, J.P., Theelen, T.L. et al. Differential regulation of angiogenic cellular processes and claudin-5 by histamine and VEGF via PI3K-signaling, transcription factor SNAI2 and interleukin-8. Angiogenesis 20, 109–124 (2017). https://doi.org/10.1007/s10456-016-9532-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10456-016-9532-7

Keywords

Navigation