Skip to main content
SpringerLink
Log in

Aryl hydrocarbon receptor agonists upregulate VEGF secretion from bronchial epithelial cells

  • Original Article
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

Abstract

Chronic airway diseases, such as asthma and chronic obstructive pulmonary disease, are characterized by airway remodeling. Vascular endothelial growth factor (VEGF) is a critical regulator of angiogenesis and vascular remodeling, important components of airway remodeling. The aryl hydrocarbon receptor (AhR) is the principle receptor for many environmental toxicants, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which may contribute to the pathogenesis of asthma and chronic obstructive pulmonary disease. However, the regulatory role of AhR on the expression of VEGF in bronchial epithelial cells (BECs) remains elusive. This study was conducted to determine the role of AhR in regulating bronchial epithelial VEGF expression, which might contribute to angiogenesis of airway remodeling. The plasma VEGF levels of asthmatic patients and healthy subjects were compared. By treating HBE-135, Beas-2B, and primary human BECs with AhR agonists, the mechanisms through which AhR modulated VEGF expression in human BECs were investigated. The plasma VEGF level was significantly higher in asthmatic patients than in healthy subjects. AhR agonists significantly upregulated VEGF secretion from human BECs, which promoted the migratory and tube-forming ability of human umbilical vein endothelial cells. The secretion of VEGF was increased via a canonical AhR pathway, followed by the 15-LOX/15-HETE/STAT3 pathway. C57BL/6JNarl mice treated with TCDD intratracheally also showed increased VEGF expression in BECs. This hitherto unrecognized pathway may provide a potential target for the treatment of airway remodeling in many pulmonary diseases, especially those related to environmental toxicants.

Key message

  • AhR agonists increase VEGF secretion from bronchial epithelial cells.

  • The mechanism involves the canonical AhR pathway and 15-LOX/15-HETE/STAT3 pathway.

  • Asthmatic patients have higher plasma VEGF level.

  • Mice treated with intratracheal TCDD show increased VEGF expression in BECs.

  • This novel regulatory pathway is a potential target for treating asthma and COPD.

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

Similar content being viewed by others

References

  1. Tsai MJ, Hsu YL, Wang TN, Wu LY, Lien CT, Hung CH, Kuo PL, Huang MS (2014) Aryl hydrocarbon receptor (AhR) agonists increase airway epithelial matrix metalloproteinase activity. J Mol Med 92:615–628

    Article  CAS  PubMed  Google Scholar 

  2. Chetta A, Olivieri D (2012) Role of inhaled steroids in vascular airway remodelling in asthma and COPD. Int J Endocrinol 2012:397693

    Article  PubMed Central  PubMed  Google Scholar 

  3. Ma B, Dela Cruz CS, Hartl D, Kang MJ, Takyar S, Homer RJ, Lee CG, Elias JA (2011) RIG-like helicase innate immunity inhibits vascular endothelial growth factor tissue responses via a type I IFN-dependent mechanism. Am J Respir Crit Care Med 183:1322–1335

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Takyar S, Vasavada H, Zhang JG, Ahangari F, Niu N, Liu Q, Lee CG, Cohn L, Elias JA (2013) VEGF controls lung Th2 inflammation via the miR-1-Mpl (myeloproliferative leukemia virus oncogene)-P-selectin axis. J Exp Med 210:1993–2010

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Lee KY, Lee KS, Park SJ, Kim SR, Min KH, Choe YH, Lee YC (2008) Clinical significance of plasma and serum vascular endothelial growth factor in asthma. J Asthma 45:735–739

    Article  CAS  PubMed  Google Scholar 

  6. Valipour A, Schreder M, Wolzt M, Saliba S, Kapiotis S, Eickhoff P, Burghuber OC (2008) Circulating vascular endothelial growth factor and systemic inflammatory markers in patients with stable and exacerbated chronic obstructive pulmonary disease. Clin Sci (Lond) 115:225–232

    Article  CAS  Google Scholar 

  7. Yoo Y, Choi IS, Byeon JH, Lee SM, La KS, Choi BM, Park SH, Choung JT (2010) Relationships of methacholine and adenosine monophosphate responsiveness with serum vascular endothelial growth factor in children with asthma. Ann Allergy Asthma Immunol 104:36–41

    Article  CAS  PubMed  Google Scholar 

  8. Kranenburg AR, de Boer WI, Alagappan VK, Sterk PJ, Sharma HS (2005) Enhanced bronchial expression of vascular endothelial growth factor and receptors (Flk-1 and Flt-1) in patients with chronic obstructive pulmonary disease. Thorax 60:106–113

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Simpson A, Custovic A, Tepper R, Graves P, Stern DA, Jones M, Hankinson J, Curtin JA, Wu J, Blekic M et al (2012) Genetic variation in vascular endothelial growth factor-a and lung function. Am J Respir Crit Care Med 185:1197–1204

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Balantic M, Rijavec M, Skerbinjek Kavalar M, Suskovic S, Silar M, Kosnik M, Korosec P (2012) Asthma treatment outcome in children is associated with vascular endothelial growth factor A (VEGFA) polymorphisms. Mol Diagn Ther 16:173–180

    Article  CAS  PubMed  Google Scholar 

  11. Yuksel H, Yilmaz O, Karaman M, Bagriyanik HA, Firinci F, Kiray M, Turkeli A, Karaman O (2013) Role of vascular endothelial growth factor antagonism on airway remodeling in asthma. Ann Allergy Asthma Immunol 110:150–155

    Article  CAS  PubMed  Google Scholar 

  12. Turner MC, Krewski D, Pope CA 3rd, Chen Y, Gapstur SM, Thun MJ (2011) Long-term ambient fine particulate matter air pollution and lung cancer in a large cohort of never-smokers. Am J Respir Crit Care Med 184:1374–1381

    Article  PubMed  Google Scholar 

  13. Hwang BF, Lee YL, Lin YC, Jaakkola JJ, Guo YL (2005) Traffic related air pollution as a determinant of asthma among Taiwanese school children. Thorax 60:467–473

    Article  PubMed Central  PubMed  Google Scholar 

  14. Nishimura KK, Galanter JM, Roth LA, Oh SS, Thakur N, Nguyen EA, Thyne S, Farber HJ, Serebrisky D, Kumar R et al (2013) Early-life air pollution and asthma risk in minority children. The GALA II and SAGE II studies. Am J Respir Crit Care Med 188:309–318

    Article  PubMed Central  PubMed  Google Scholar 

  15. Brunekreef B, Forsberg B (2005) Epidemiological evidence of effects of coarse airborne particles on health. Eur Respir J 26:309–318

    Article  CAS  PubMed  Google Scholar 

  16. Gao Y, Chan EY, Li L, Lau PW, Wong TW (2014) Chronic effects of ambient air pollution on respiratory morbidities among Chinese children: a cross-sectional study in Hong Kong. BMC Public Health 14:105

    Article  PubMed Central  PubMed  Google Scholar 

  17. Sunyer J, Saez M, Murillo C, Castellsague J, Martinez F, Anto JM (1993) Air pollution and emergency room admissions for chronic obstructive pulmonary disease: a 5-year study. Am J Epidemiol 137:701–705

    CAS  PubMed  Google Scholar 

  18. Makra L, Matyasovszky I, Balint B (2012) Association of allergic asthma emergency room visits with the main biological and chemical air pollutants. Sci Total Environ 432:288–296

    Article  CAS  PubMed  Google Scholar 

  19. Chiba T, Uchi H, Yasukawa F, Furue M (2011) Role of the arylhydrocarbon receptor in lung disease. Int Arch Allergy Immunol 155(Suppl 1):129–134

    Article  CAS  PubMed  Google Scholar 

  20. Wong PS, Vogel CF, Kokosinski K, Matsumura F (2010) Arylhydrocarbon receptor activation in NCI-H441 cells and C57BL/6 mice: possible mechanisms for lung dysfunction. Am J Respir Cell Mol Biol 42:210–217

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Bertazzi PA, Consonni D, Bachetti S, Rubagotti M, Baccarelli A, Zocchetti C, Pesatori AC (2001) Health effects of dioxin exposure: a 20-year mortality study. Am J Epidemiol 153:1031–1044

    Article  CAS  PubMed  Google Scholar 

  22. Nguyen LP, Bradfield CA (2008) The search for endogenous activators of the aryl hydrocarbon receptor. Chem Res Toxicol 21:102–116

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Henry EC, Bemis JC, Henry O, Kende AS, Gasiewicz TA (2006) A potential endogenous ligand for the aryl hydrocarbon receptor has potent agonist activity in vitro and in vivo. Arch Biochem Biophys 450:67–77

    Article  CAS  PubMed  Google Scholar 

  24. Hoshino M, Nakamura Y, Hamid QA (2001) Gene expression of vascular endothelial growth factor and its receptors and angiogenesis in bronchial asthma. J Allergy Clin Immunol 107:1034–1038

    Article  CAS  PubMed  Google Scholar 

  25. Zhao J, Maskrey B, Balzar S, Chibana K, Mustovich A, Hu H, Trudeau JB, O'Donnell V, Wenzel SE (2009) Interleukin-13-induced MUC5AC is regulated by 15-lipoxygenase 1 pathway in human bronchial epithelial cells. Am J Respir Crit Care Med 179:782–790

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Singh NK, Wang D, Kundumani-Sridharan V, Van Quyen D, Niu J, Rao GN (2011) 15-Lipoxygenase-1-enhanced Src-Janus kinase 2-signal transducer and activator of transcription 3 stimulation and monocyte chemoattractant protein-1 expression require redox-sensitive activation of epidermal growth factor receptor in vascular wall remodeling. J Biol Chem 286:22478–22488

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Bui P, Solaimani P, Wu X, Hankinson O (2012) 2,3,7,8-Tetrachlorodibenzo-p-dioxin treatment alters eicosanoid levels in several organs of the mouse in an aryl hydrocarbon receptor-dependent fashion. Toxicol Appl Pharmacol 259:143–151

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Dong B, Matsumura F (2008) Roles of cytosolic phospholipase A2 and Src kinase in the early action of 2,3,7,8-tetrachlorodibenzo-p-dioxin through a nongenomic pathway in MCF10A cells. Mol Pharmacol 74:255–263

    Article  CAS  PubMed  Google Scholar 

  29. Takeuchi A, Takeuchi M, Oikawa K, Sonoda KH, Usui Y, Okunuki Y, Takeda A, Oshima Y, Yoshida K, Usui M et al (2009) Effects of dioxin on vascular endothelial growth factor (VEGF) production in the retina associated with choroidal neovascularization. Invest Ophthalmol Vis Sci 50:3410–3416

    Article  PubMed  Google Scholar 

  30. Roman AC, Carvajal-Gonzalez JM, Rico-Leo EM, Fernandez-Salguero PM (2009) Dioxin receptor deficiency impairs angiogenesis by a mechanism involving VEGF-A depletion in the endothelium and transforming growth factor-beta overexpression in the stroma. J Biol Chem 284:25135–25148

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Wang TN, Lin MC, Wu CC, Leung SY, Huang MS, Chuang HY, Lee CH, Wu DC, Ho PS, Ko AM et al (2010) Risks of exposure to occupational asthmogens in atopic and nonatopic asthma: a case-control study in Taiwan. Am J Respir Crit Care Med 182:1369–1376

    Article  CAS  PubMed  Google Scholar 

  32. Sohn SW, Lee HS, Park HW, Chang YS, Kim YK, Cho SH, Kim YY, Min KU (2008) Evaluation of cytokine mRNA in induced sputum from patients with allergic rhinitis: relationship to airway hyperresponsiveness. Allergy 63:268–273

    Article  CAS  PubMed  Google Scholar 

  33. Forsythe JA, Jiang BH, Iyer NV, Agani F, Leung SW, Koos RD, Semenza GL (1996) Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol 16:4604–4613

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Ichihara S, Yamada Y, Ichihara G, Nakajima T, Li P, Kondo T, Gonzalez FJ, Murohara T (2007) A role for the aryl hydrocarbon receptor in regulation of ischemia-induced angiogenesis. Arterioscler Thromb Vasc Biol 27:1297–1304

    Article  CAS  PubMed  Google Scholar 

  35. Fritz WA, Lin TM, Peterson RE (2008) The aryl hydrocarbon receptor (AhR) inhibits vanadate-induced vascular endothelial growth factor (VEGF) production in TRAMP prostates. Carcinogenesis 29:1077–1082

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Ma C, Li Y, Ma J, Liu Y, Li Q, Niu S, Shen Z, Zhang L, Pan Z, Zhu D (2011) Key role of 15-lipoxygenase/15-hydroxyeicosatetraenoic acid in pulmonary vascular remodeling and vascular angiogenesis associated with hypoxic pulmonary hypertension. Hypertension 58:679–688

    Article  CAS  PubMed  Google Scholar 

  37. Profita M, Sala A, Riccobono L, Paterno A, Mirabella A, Bonanno A, Guerrera D, Pace E, Bonsignore G, Bousquet J et al (2000) 15-Lipoxygenase expression and 15(S)-hydroxyeicoisatetraenoic acid release and reincorporation in induced sputum of asthmatic subjects. J Allergy Clin Immunol 105:711–716

    Article  CAS  PubMed  Google Scholar 

  38. Pages G, Pouyssegur J (2005) Transcriptional regulation of the vascular endothelial growth factor gene–a concert of activating factors. Cardiovasc Res 65:564–573

    Article  CAS  PubMed  Google Scholar 

  39. Niu G, Wright KL, Huang M, Song L, Haura E, Turkson J, Zhang S, Wang T, Sinibaldi D, Coppola D et al (2002) Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis. Oncogene 21:2000–2008

    Article  CAS  PubMed  Google Scholar 

  40. Xu B, Bhattacharjee A, Roy B, Xu HM, Anthony D, Frank DA, Feldman GM, Cathcart MK (2003) Interleukin-13 induction of 15-lipoxygenase gene expression requires p38 mitogen-activated protein kinase-mediated serine 727 phosphorylation of Stat1 and Stat3. Mol Cell Biol 23:3918–3928

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Funding

This study was supported by grants from the Kaohsiung Medical University Hospital (KMUH101-1M12, KMUH102-2T06 and KMUH102-2M07), the Aim for the Top Journals Grant, Kaohsiung Medical University Research Foundation (KMU-DT103008), National Science Council (NSC 101-2320-B-037-043-MY3), and Ministry of Science and Technology (MOST 104-2314-B-037-005).

Conflict of interest

The authors declare no conflicts of interest.

Author information

Author notes

    Authors and Affiliations

    1. Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, No. 100, Shih-Chuan 1st road, 807, Kaohsiung, Taiwan

      Ming-Ju Tsai, Ya-Ling Hsu & Ming-Shyan Huang

    2. Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan

      Ming-Ju Tsai, Yi-Shiuan Lin & Ming-Shyan Huang

    3. Department of Public Health, College of Health Science, Kaohsiung Medical University, Kaohsiung, Taiwan

      Tsu-Nai Wang

    4. Center of Excellence for Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

      Tsu-Nai Wang, Po-Lin Kuo & Ming-Shyan Huang

    5. Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

      Po-Lin Kuo

    6. Department of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

      Ming-Shyan Huang

    Authors
    1. Ming-Ju Tsai
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Tsu-Nai Wang
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Yi-Shiuan Lin
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Po-Lin Kuo
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Ya-Ling Hsu
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Ming-Shyan Huang
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding authors

    Correspondence to Ya-Ling Hsu or Ming-Shyan Huang.

    Additional information

    Ya-Ling Hsu and Ming-Shyan Huang contributed equally to this work.

    Electronic supplementary material

    Below is the link to the electronic supplementary material.

    ESM 1

    (PDF 340 kb)

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Tsai, MJ., Wang, TN., Lin, YS. et al. Aryl hydrocarbon receptor agonists upregulate VEGF secretion from bronchial epithelial cells. J Mol Med 93, 1257–1269 (2015). https://doi.org/10.1007/s00109-015-1304-0

    Download citation

    • Received:

    • Revised:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s00109-015-1304-0

    Keywords

    Search

    Navigation