Potential Role of Angiogenesis and Lymphangiogenesis in Atopic Dermatitis: Evidence from Human Studies and Lessons from an Animal Model of Human Disease



Atopic dermatitis (AD) is a skin condition characterized by chronic inflammatory cell infiltration and skin pruritus. Angiogenesis and lymphangiogenesis are key features in the development of AD because blood and lymphatic vessels provide pathways for immune cell transport. Crucial interactions among selectins, integrins, cytokines, chemokines, and various growth factors promote the growth of the vasculature resulting in exacerbation of the AD condition. Although research on angiogenesis and lymphangiogensis in relation to human AD is limited in scope and depth, we explain the role of vasculature in AD as a foundation to introduce our evidence of neovascularization in an animal model of the disease. In this review, we attempt to delineate the potential roles of angiogenesis and lymphoangiogenesis in AD to target new areas of therapeutic intervention.


Atopic dermatitis Angiogenesis Lymphangiogenesis VEGF IL-4 



Atopic dermatitis






Before onset


Cell adhesion molecule


Evans Blue


Endothelial cell


Early lesion


Fibroblast growth factor-beta


Human adult high calcium low temperature keratinoctyes


Interendothelial junctional cleft


Immunoglobulin super family cell adhesion molecules




Lymphatic endothelial cells


Late lesion


Lymphatic vessel endothelial hyaluronan receptor


Macrophage chemotactic protein-1






Proteinase-activated receptor 2


Platelet endothelial cell adhesion molecule-1


Dermal post-capillary venules




Scanning electronic microscopy


Single nucleotide polymorphisms


Transitional electron microscopy




Tight junction


Vascular adhesion protein-1


Vascular endothelial cell growth factor-A, B, C, D

VEGFR-1, 2, 3

Vascular endothelial cell growth factor receptor-1, 2, 3


  1. 1.
    Chan LS. Atopic dermatitis in 2008. Curr Dir Autoimmun. 2008;10:76–118.CrossRefPubMedGoogle Scholar
  2. 2.
    Department of Health. Handout on health: atopic dermatitis. [Homepage on the Internet]. c2011 [updated 2011, August]. Available from
  3. 3.
    Eichenfield LF, Hanifin JM, Beck LA, et al. Atopic dermatitis and asthma: parallels in the evolution of treatment. Pediatrics. 2003;111:608–16.CrossRefPubMedGoogle Scholar
  4. 4.
    Spergel JM, Paller AS. Atopic dermatitis and the atopic march. J Allergy Clin Immunol. 2003;112:S118–27.CrossRefPubMedGoogle Scholar
  5. 5.
    Guttman-Yassky E, Nograles KE, Krueger JG. Contrasting pathogenesis of atopic dermatitis and psoriasis–part II: immune cell subsets and therapeutic concepts. J Allergy Clin Immunol. 2011;127:1420–32.CrossRefPubMedGoogle Scholar
  6. 6.
    Guttman-Yassky E, Nograles KE, Krueger JG. Contrasting pathogenesis of atopic dermatitis and psoriasis–part I: clinical and pathologic concepts. J Allergy Clin Immunol. 2011;127:1110–8.CrossRefPubMedGoogle Scholar
  7. 7.
    Chen L, Martinez O, Overbergh L, et al. Early up-regulation of Th2 cytokines and late surge of Th1 cytokines in an atopic dermatitis model. Clin Exp Immunol. 2004;138:375–87.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Szekanecz Z, Koch AE. Mechanisms of disease: angiogenesis in inflammatory diseases. Nat Clin Pract Rheumatol. 2007;3:635–43.CrossRefPubMedGoogle Scholar
  9. 9.
    Velasco P, Lange-Asschenfeldt B. Dermatological aspects of angiogenesis. Br J Dermatol. 2002;147:841–52.CrossRefPubMedGoogle Scholar
  10. 10.
    Ala A, Dhillon AP, Hodgson HJ. Role of cell adhesion molecules in leukocyte recruitment in the liver and gut. Int J Exp Pathol. 2003;84:1–16.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Wakita H, Sakamoto T, Tokura Y, et al. E-selectin and vascular cell adhesion molecule-1 as critical adhesion molecules for infiltration of T lymphocytes and eosinophils in atopic dermatitis. J Cutan Pathol. 1994;21:33–9.CrossRefPubMedGoogle Scholar
  12. 12.
    Steinhoff M, Steinhoff A, Homey B, et al. Role of vasculature in atopic dermatitis. J Allergy Clin Immunol. 2006;118:190–7.CrossRefPubMedGoogle Scholar
  13. 13.
    Gutgesell C, Heise S, Seubert A, et al. Comparison of different activity parameters in atopic dermatitis: correlation with clinical scores. Br J Dermatol. 2002;147:914–9.CrossRefPubMedGoogle Scholar
  14. 14.
    de Vries IJ, Langeveld-Wildschut EG, van Reijsen FC, et al. Adhesion molecule expression on skin endothelia in atopic dermatitis: effects of TNF-alpha and IL-4. J Allergy Clin Immunol. 1998;102:461–8.CrossRefPubMedGoogle Scholar
  15. 15.
    Madej A, Reich A, Orda A, et al. Expression of vascular adhesion protein-1 in atopic eczema. Int Arch Allergy Immunol. 2006;139:114–21.CrossRefPubMedGoogle Scholar
  16. 16.
    Bieber T. Atopic dermatitis: a paradigmatic allergic skin disease. Mediators Inflamm. 2001;10:291–2.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Jung K, Imhof BA, Linse R, et al. Adhesion molecules in atopic dermatitis: upregulation of alpha6 integrin expression in spontaneous lesional skin as well as in atopen, antigen and irritative induced patch test reactions. Int Arch Allergy Immunol. 1997;113:495–504.CrossRefPubMedGoogle Scholar
  18. 18.
    Jung K, Linse F, Heller R, et al. Adhesion molecules in atopic dermatitis: VCAM-1 and ICAM-1 expression is increased in healthy-appearing skin. Allergy. 1996;51:452–60.CrossRefPubMedGoogle Scholar
  19. 19.
    Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med. 1995;1:27–31.CrossRefPubMedGoogle Scholar
  20. 20.
    Genovese A, Detoraki A, Granata F, et al. Angiogenesis, lymphangiogenesis and atopic dermatitis. Chem Immunol Allergy. 2012;96:50–60.CrossRefPubMedGoogle Scholar
  21. 21.
    Carmeliet P, Jain RK. Molecular mechanisms and clinical applications of angiogenesis. Nature. 2011;473:298–307.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Gluzman-Poltorak Z, Cohen T, Herzog Y, et al. Neuropilin-2 is a receptor for the vascular endothelial growth factor (VEGF) forms VEGF-145 and VEGF-165 [corrected]. J Biol Chem. 2000;275:18040–5.CrossRefPubMedGoogle Scholar
  23. 23.
    Soker S, Takashima S, Miao HQ, et al. Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor. Cell. 1998;92:735–45.CrossRefPubMedGoogle Scholar
  24. 24.
    Herzog Y, Kalcheim C, Kahane N, et al. Differential expression of neuropilin-1 and neuropilin-2 in arteries and veins. Mech Dev. 2001;109:115–9.CrossRefPubMedGoogle Scholar
  25. 25.
    Amarbayasgalan T, Takahashi H, Dekio I, et al. Content of vascular endothelial growth factor in stratum corneum well correlates to local severity of acute inflammation in patients with atopic dermatitis. Int Arch Allergy Immunol. 2012;157:251–8.CrossRefPubMedGoogle Scholar
  26. 26.
    Kay AB. Calcitonin gene-related peptide- and vascular endothelial growth factor-positive inflammatory cells in late-phase allergic skin reactions in atopic subjects. J Allergy Clin Immunol. 2011;127:232–7.CrossRefPubMedGoogle Scholar
  27. 27.
    Shahbazi M, Fryer AA, Pravica V, et al. Vascular endothelial growth factor gene polymorphisms are associated with acute renal allograft rejection. J Am Soc Nephrol. 2002;13:260–4.PubMedGoogle Scholar
  28. 28.
    Detoraki A, Staiano RI, Granata F, et al. Vascular endothelial growth factors synthesized by human lung mast cells exert angiogenic effects. J Allergy Clin Immunol. 2009;123:1142–9. 9 e1-5.CrossRefPubMedGoogle Scholar
  29. 29.
    Steinhoff M, Neisius U, Ikoma A, et al. Proteinase-activated receptor-2 mediates itch: a novel pathway for pruritus in human skin. J Neurosci. 2003;23:6176–80.PubMedGoogle Scholar
  30. 30.
    Groneberg DA, Bester C, Grutzkau A, et al. Mast cells and vasculature in atopic dermatitis–potential stimulus of neoangiogenesis. Allergy. 2005;60:90–7.CrossRefPubMedGoogle Scholar
  31. 31.
    Bao L, Shi VY, Chan LS. IL-4 up-regulates epidermal chemotactic, angiogenic, and pro-inflammatory genes and down-regulates antimicrobial genes in vivo and in vitro: relevant in the pathogenesis of atopic dermatitis. Cytokine. 2013;61:419–25.CrossRefPubMedGoogle Scholar
  32. 32.
    Takahashi H, Numasaki M, Lotze MT, et al. Interleukin-17 enhances bFGF-, HGF- and VEGF-induced growth of vascular endothelial cells. Immunol Lett. 2005;98:189–93.CrossRefPubMedGoogle Scholar
  33. 33.
    Sismanopoulos N, Delivanis DA, Alysandratos KD, et al. IL-9 induces VEGF secretion from human mast cells and IL-9/IL-9 receptor genes are overexpressed in atopic dermatitis. PLoS One. 2012;7:e33271.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Homey B, Steinhoff M, Ruzicka T, et al. Cytokines and chemokines orchestrate atopic skin inflammation. J Allergy Clin Immunol. 2006;118:178–89.CrossRefPubMedGoogle Scholar
  35. 35.
    Chan LS, Robinson N, Xu L. Expression of interleukin-4 in the epidermis of transgenic mice results in a pruritic inflammatory skin disease: an experimental animal model to study atopic dermatitis. J Invest Dermatol. 2001;117:977–83.CrossRefPubMedGoogle Scholar
  36. 36.
    Hanifin JM, Rajka G. Diagnostic features of atopic dermatitis. Acta Derm Venereol Suppl (Stockh). 1980;92:4.Google Scholar
  37. 37.
    Henno A, Blacher S, Lambert CA, et al. Histological and transcriptional study of angiogenesis and lymphangiogenesis in uninvolved skin, acute pinpoint lesions and established psoriasis plaques: an approach of vascular development chronology in psoriasis. J Dermatol Sci. 2010;57:162–9.CrossRefPubMedGoogle Scholar
  38. 38.
    Chen L, Marble DJ, Agha R, et al. The progression of inflammation parallels the dermal angiogenesis in a keratin 14 IL-4-transgenic model of atopic dermatitis. Microcirculation. 2008;15:49–64.CrossRefPubMedGoogle Scholar
  39. 39.
    Agha-Majzoub R, Becker RP, Schraufnagel DE, et al. Angiogenesis: the major abnormality of the keratin-14 IL-4 transgenic mouse model of atopic dermatitis. Microcirculation. 2005;12:455–76.CrossRefPubMedGoogle Scholar
  40. 40.
    Shi VY, Bao L, Chan LS. Inflammation-Driven Dermal Lymphangiogenesis in Atopic Dermatitis is Associated with CD11b+ Macrophage Recruitment and VEGF-C Up-regulation in the IL-4-Transgenic Mouse Model. Microcirculation. 2012;19:567–79.CrossRefPubMedGoogle Scholar
  41. 41.
    Stephan CC, Brock TA. Vascular endothelial growth factor, a multifunctional polypeptide. P R Health Sci J. 1996;15:169–78.PubMedGoogle Scholar
  42. 42.
    Frank S, Hubner G, Breier G, et al. Regulation of vascular endothelial growth factor expression in cultured keratinocytes. Implications for normal and impaired wound healing. J Biol Chem. 1995;270:12607–13.CrossRefPubMedGoogle Scholar
  43. 43.
    Trompezinski S, Denis A, Vinche A, et al. IL-4 and interferon-gamma differentially modulate vascular endothelial growth factor release from normal human keratinocytes and fibroblasts. Exp Dermatol. 2002;11:224–31.CrossRefPubMedGoogle Scholar
  44. 44.
    Detmar M, Yeo KT, Nagy JA, et al. Keratinocyte-derived vascular permeability factor (vascular endothelial growth factor) is a potent mitogen for dermal microvascular endothelial cells. J Invest Dermatol. 1995;105:44–50.CrossRefPubMedGoogle Scholar
  45. 45.
    Maruyama K, Ii M, Cursiefen C, et al. Inflammation-induced lymphangiogenesis in the cornea arises from CD11b-positive macrophages. J Clin Invest. 2005;115:2363–72.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Granata F, Frattini A, Loffredo S, et al. Production of vascular endothelial growth factors from human lung macrophages induced by group IIA and group X secreted phospholipases A2. J Immunol. 2010;184:5232–41.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag London Ltd. 2017

Authors and Affiliations

  • Huayi Zhang
    • 1
  • Vivian Y. Shi
    • 1
  • Lawrence S. Chan
    • 1
    • 2
    • 3
    • 4
  1. 1.Department of DermatologyUniversity of Illinois College of MedicineChicagoUSA
  2. 2.Department of Microbiology/ImmunologyUniversity of Illinois College of MedicineChicagoUSA
  3. 3.Medicine ServicesJesse Brown VA Medical CenterChicagoUSA
  4. 4.Captain James Lovell Federal Health Care CenterNorth ChicagoUSA

Personalised recommendations