Angiogenesis and Pathogenesis of Port Wine Stain and Infantile Hemangiomas

  • Wangcun Jia
  • Carol Cheng
  • Wenbin Tan
  • Martin C. MihmJr
  • J. Stuart Nelson


This chapter focuses on the angiogenesis and vasculogenesis involved in the pathophysiological processes and treatments of two common congenital vascular anomalies, namely port wine stain (PWS) and infantile hemangiomas (IH). PWS occur as pink/red macules in childhood but darken progressively to purple with subsequent skin thickening and the development of vascular nodules. Dilatation of postcapillary venules in PWS is likely caused by a deficiency of local nerve innervation. Although the pulsed dye laser has revolutionized PWS treatment, complete clearance is rarely achieved due to regrowth and reperfusion of injured blood vessels. Angiogenic signaling pathways activated after laser exposure will be discussed and the animal and clinical results of a new therapeutic strategy for PWS, combined laser exposure and administration of an anti-angiogenic agent will be presented. IH are tumors of infancy with a unique life cycle characterized by rapid proliferation followed by slow spontaneous involution. Phase-specific markers have been identified, including GLUT-1 and more recently indoleamine 2,3-dioxygenase associated with involution. The current understanding of the pathogenesis includes a close relationship with placental origin, role of hypoxia in stimulating development and somatic mutations in early development of the tumors.


Vascular anomaly Port wine stain Hemangioma Pulsed dye laser Rapamycin GLUT-1 Indoleamine 2,3-dioxygenase Placenta 


  1. 1.
    Mulliken JB, Glowacki J. Hemangiomas and vascular malformations in infants and children: a classification based on endothelial characteristics. Plast Reconstr Surg. 1982;69(3):412–22.PubMedCrossRefGoogle Scholar
  2. 2.
    Jacobs AH, Walton RG. The incidence of birthmarks in the neonate. Pediatrics. 1976;58:218–22.PubMedGoogle Scholar
  3. 3.
    Mulliken JB, Young AR. Vascular birthmarks–hemangiomas and malformations. Philadelphia: W.B. Saunders Co.; 1988.Google Scholar
  4. 4.
    Pratt AG. Birthmarks in infants. Arch Derm Syphilol. 1953;67:302–5.CrossRefGoogle Scholar
  5. 5.
    Alper JC, Holmes LB. The incidence and significance of birthmarks in a cohort of 4641 newborns. Pediatr Dermatol. 1986;1:58–68.CrossRefGoogle Scholar
  6. 6.
    Kalick SM. Toward an interdisciplinary psychology of appearances. Psychiatry. 1978;41(3):243–53.PubMedCrossRefGoogle Scholar
  7. 7.
    Heller A, Rafman S, Zvagulis I, Pless IB. Birth-defects and psychosocial adjustment. Am J Dis Child. 1985;139(3):257–63.PubMedGoogle Scholar
  8. 8.
    Malm M, Carlberg M. Port-wine stain – a surgical and psychological problem. Ann Plast Surg. 1988;20(6):512–6.PubMedCrossRefGoogle Scholar
  9. 9.
    Minkis K, Geronemus RG, Hale EK. Port wine stain progression: a potential consequence of delayed and inadequate treatment? Lasers Surg Med. 2009;41(6):423–6.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Geronemus RG, Ashinoff R. The medical necessity of evaluation and treatment of port-wine stains. J Dermatol Surg Oncol. 1991;17(1):76–9.PubMedCrossRefGoogle Scholar
  11. 11.
    Barsky SH, Rosen S, Geer DE, Noe JM. The nature and evolution of port wine stains: a computer-assisted study. J Invest Dermatol. 1980;74(3):154–7.PubMedCrossRefGoogle Scholar
  12. 12.
    Braverman IM, Kehyen A. Ultrastructure and 3-dimensional reconstruction of several macular and papular telangiectases. J Invest Dermatol. 1983;81(6):489–97.PubMedCrossRefGoogle Scholar
  13. 13.
    Schneider BV, Mitsuhashi Y, Schnyder UW. Ultrastructural observations in port wine stains. Arch Dermatol Res. 1988;280(6):338–45.PubMedCrossRefGoogle Scholar
  14. 14.
    Tallman B, Tan OT, Morelli JG, Piepenbrink J, Stafford TJ, Trainor S, Weston WL. Location of port-wine stains and the likelihood of ophthalmic and/or central nervous system complications. Pediatrics. 1991;87(3):323–7.PubMedGoogle Scholar
  15. 15.
    Smoller BR, Rosen S. Port-wine stains. A disease of altered neural modulation of blood vessels? Arch Dermatol. 1986;122(2):177–9.PubMedCrossRefGoogle Scholar
  16. 16.
    Rydh M, Malm M, Jernbeck J, Dalsgaard CJ. Ectatic blood vessels in port-wine stains lack innervation: possible role in pathogenesis. Plast Reconstr Surg. 1991;87(3):419–22.PubMedCrossRefGoogle Scholar
  17. 17.
    Selim MM, Kelly KM, Nelson JS, Wendelschafer-Crabb G, Kennedy WR, Zelickson BD. Confocal microscopy study of nerves and blood vessels in untreated and treated port wine stains: preliminary observations. Dermatol Surg. 2004;30(6):892–7.PubMedGoogle Scholar
  18. 18.
    Rosen S, Smoller B. Pathogenesis of port wine stains. A new hypothesis. Med Hypotheses. 1987;22(4):365–8.PubMedCrossRefGoogle Scholar
  19. 19.
    Anderson RR, Parrish JA. Selective photothermolysis – precise microsurgery by selective absorption of pulsed radiation. Science. 1983;220(4596):524–7.PubMedCrossRefGoogle Scholar
  20. 20.
    Morelli JG, Tan OT, Garden J, Margolis R, Seki Y, Boll J, Carney JM, Anderson RR, Furumoto H, Parrish JA. Tunable dye laser (577 nm) treatment of port wine stains. Lasers Surg Med. 1986;6(1):94–9.PubMedCrossRefGoogle Scholar
  21. 21.
    Tan OT, Morrison P, Kurban AK. 585-Nm for the treatment of port-wine stains. Plast Reconstr Surg. 1990;86(6):1112–7.PubMedCrossRefGoogle Scholar
  22. 22.
    Nelson JS, Milner TE, Anvari B, Tanenbaum BS, Kimel S, Svaasand LO, Jacques SL. Dynamic epidermal cooling during pulsed laser treatment of port-wine stain: a new methodology with preliminary clinical evaluation. Arch Dermatol. 1995;131(6):695–700.PubMedCrossRefGoogle Scholar
  23. 23.
    Chang CJ, Nelson JS. Cryogen spray cooling and higher fluence pulsed dye laser treatment improve port-wine stain clearance while minimizing epidermal damage. Dermatol Surg. 1999;25(10):767–72.PubMedCrossRefGoogle Scholar
  24. 24.
    van der Horst CMAM, Koster PHL, de Borgie CAJM, Bossuyt PMM, van Gemert MJC. Effect of the timing of treatment of port-wine stains with the flash-lamp-pumped pulsed dye-laser. New Engl J Med. 1998;338(15):1028–33.PubMedCrossRefGoogle Scholar
  25. 25.
    Yohn JJ, Huff JC, Aeling JL, Walsh P, Morelli JG. Lesion size is a factor for determining the rate of port-wine stain clearing following pulsed dye laser treatment in adults. Cutis. 1997;59(5):267–70.PubMedGoogle Scholar
  26. 26.
    Lanigan SW, Taibjee SM. Recent advances in laser treatment of port-wine stains. Brit J Dermatol. 2004;151(3):527–33.CrossRefGoogle Scholar
  27. 27.
    Fiskerstrand EJ, Svaasand LO, Kopstad G, Dalaker M, Norvang LT, Volden G. Laser treatment of port wine stains: therapeutic outcome in relation to morphological parameters. Br J Dermatol. 1996;134(6):1039–43.PubMedCrossRefGoogle Scholar
  28. 28.
    Hohenleutner U, Hilbert M, Wlotzke U, Landthaler M. Epidermal damage and limited coagulation depth with the flashlamp-pumped pulsed dye-laser – a histochemical-study. J Invest Dermatol. 1995;104(5):798–802.PubMedCrossRefGoogle Scholar
  29. 29.
    Jia W, Choi B, Franco W, Lotfi J, Majaron B, Aguilar G, Nelson JS. Treatment of cutaneous vascular lesions using multiple-intermittent cryogen spurts and two-wavelength laser pulses: numerical and animal studies. Lasers Surg Med. 2007;39(6):494–503.PubMedCrossRefGoogle Scholar
  30. 30.
    Huikeshoven M, Koster PHL, de Borgie C, Beek JF, van Gemert MJC, van der Horst C. Redarkening of port-wine stains 10 years after pulsed-dye-laser treatment. New Engl J Med. 2007;356(12):1235–40.PubMedCrossRefGoogle Scholar
  31. 31.
    Phung TL, Oble DA, Jia W, Benjamin LE, Mihm Jr MC, Nelson JS. Can the wound healing response of human skin be modulated after laser treatment and the effects of exposure extended? Implications on the combined use of the pulsed dye laser and a topical angiogenesis inhibitor for treatment of port wine stain birthmarks. Lasers Surg Med. 2008;40(1):1–5.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Jia W, Sun V, Tran N, Choi B, Liu SW, Mihm Jr MC, Phung TL, Nelson JS. Long-term blood vessel removal with combined laser and topical rapamycin antiangiogenic therapy: implications for effective port wine stain treatment. Lasers Surg Med. 2010;42(2):105–12.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Coulon C, Georgiadou M, Roncal C, De Bock K, Langenberg T, Carmeliet P. From vessel sprouting to normalization: role of the prolyl hydroxylase domain protein/hypoxia-inducible factor oxygen-sensing machinery. Arterioscler Thromb Vasc Biol. 2010;30(12):2331–6.PubMedCrossRefGoogle Scholar
  34. 34.
    Fong GH. Regulation of angiogenesis by oxygen sensing mechanisms. J Mol Med (Berl). 2009;87(6):549–60.CrossRefGoogle Scholar
  35. 35.
    Pugh CW, Ratcliffe PJ. Regulation of angiogenesis by hypoxia: role of the HIF system. Nat Med. 2003;9(6):677–84.PubMedCrossRefGoogle Scholar
  36. 36.
    Semenza GL. Hypoxia-inducible factors in physiology and medicine. Cell. 2012;148(3):399–408.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Wang GL, Jiang BH, Rue EA, Semenza GL. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci U S A. 1995;92(12):5510–4.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Wiener CM, Booth G, Semenza GL. In vivo expression of mRNAs encoding hypoxia-inducible factor 1. Biochem Biophys Res Commun. 1996;225(2):485–8.PubMedCrossRefGoogle Scholar
  39. 39.
    Palmer LA, Semenza GL, Stoler MH, Johns RA. Hypoxia induces type II NOS gene expression in pulmonary artery endothelial cells via HIF-1. Am J Physiol. 1998;274(2 Pt 1):L212–9.PubMedGoogle Scholar
  40. 40.
    Bergeron M, Yu AY, Solway KE, Semenza GL, Sharp FR. Induction of hypoxia-inducible factor-1 (HIF-1) and its target genes following focal ischaemia in rat brain. Eur J Neurosci. 1999;11(12):4159–70.PubMedCrossRefGoogle Scholar
  41. 41.
    Pialoux V, Mounier R, Brown AD, Steinback CD, Rawling JM, Poulin MJ. Relationship between oxidative stress and HIF-1 alpha mRNA during sustained hypoxia in humans. Free Radic Biol Med. 2009;46(2):321–6.PubMedCrossRefGoogle Scholar
  42. 42.
    Zmonarski SC, Boratynska M, Rabczynski J, Kazimierczak K, Klinger M. Regression of Kaposi’s sarcoma in renal graft recipients after conversion to sirolimus treatment. Transplant Proc. 2005;37(2):964–6.PubMedCrossRefGoogle Scholar
  43. 43.
    Land SC, Tee AR. Hypoxia-inducible factor 1alpha is regulated by the mammalian target of rapamycin (mTOR) via an mTOR signaling motif. J Biol Chem. 2007;282(28):20534–43.PubMedCrossRefGoogle Scholar
  44. 44.
    Tan W, Jia W, Sun V, Mihm MC, Nelson JS. Topical rapamycin suppresses the angiogenesis pathways induced by pulsed dye laser: mechanisms of inhibition of regeneration and revascularization of photocoagulated blood vessels lasers in surgery and medicine. Lasers Surg Med. 2012;44(10):796–804.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Carmeliet P, Jain RK. Molecular mechanisms and clinical applications of angiogenesis. Nature. 2011;473(7347):298–307.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Koch S, Tugues S, Li X, Gualandi L, Claesson-Welsh L. Signal transduction by vascular endothelial growth factor receptors. Biochem J. 2011;437(2):169–83.PubMedCrossRefGoogle Scholar
  47. 47.
    Sekiguchi Y, Zhang J, Patterson S, Liu L, Hamada C, Tomino Y, Margetts PJ. Rapamycin inhibits transforming growth factor beta induced peritoneal angiogenesis by blocking the secondary hypoxic response. J Cell Mol Med. 2012;16(8):12.CrossRefGoogle Scholar
  48. 48.
    Semenza GL. HIF-1: using two hands to flip the angiogenic switch. Cancer Metastasis Rev. 2000;19(1–2):59–65.PubMedCrossRefGoogle Scholar
  49. 49.
    Semenza GL. Vascular responses to hypoxia and ischemia. Arterioscler Thromb Vasc Biol. 2010;30(4):648–52.PubMedCrossRefGoogle Scholar
  50. 50.
    Kilic E, Kilic U, Wang Y, Bassetti CL, Marti HH, Hermann DM. The phosphatidylinositol-3 kinase/Akt pathway mediates VEGF’s neuroprotective activity and induces blood brain barrier permeability after focal cerebral ischemia. FASEB J. 2006;20(8):1185–7.PubMedCrossRefGoogle Scholar
  51. 51.
    Tan W, Jia W, Sun V, Nelson JS. Rapamycin reverses the process of regeneration and revascularization of photocoagulated blood vessels in an animal model. American Society for Laser Medicine and Surgery Annual Conference, vol. 44. Kissimmee: Wiley; 2012. p. 39.Google Scholar
  52. 52.
    Loewe R, Oble DA, Valero T, Zukerberg L, Mihm Jr MC, Nelson JS. Stem cell marker upregulation in normal cutaneous vessels following pulsed-dye laser exposure and its abrogation by concurrent rapamycin administration: implications for treatment of port-wine stain birthmarks. J Cutan Pathol. 2010;37(Suppl 1):76–82.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Ribatti D. The involvement of endothelial progenitor cells in tumor angiogenesis. J Cell Mol Med. 2004;8(3):294–300.PubMedCrossRefGoogle Scholar
  54. 54.
    Oswald J, Boxberger S, Jorgensen B, Feldmann S, Ehninger G, Bornhauser M, Werner C. Mesenchymal stem cells can be differentiated into endothelial cells in vitro. Stem Cells. 2004;22(3):377–84.PubMedCrossRefGoogle Scholar
  55. 55.
    Amoh Y, Li L, Yang M, Moossa AR, Katsuoka K, Penman S, Hoffman RM. Nascent blood vessels in the skin arise from nestin-expressing hair-follicle cells. Proc Natl Acad Sci U S A. 2004;101(36):13291–5.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Shimizu T, Sugawara K, Tosaka M, Imai H, Hoya K, Takeuchi T, Sasaki T, Saito N. Nestin expression in vascular malformations: a novel marker for proliferative endothelium. Neurol Med Chir (Tokyo). 2006;46(3):111–7.CrossRefGoogle Scholar
  57. 57.
    Sugawara K, Kurihara H, Negishi M, Saito N, Nakazato Y, Sasaki T, Takeuchi T. Nestin as a marker for proliferative endothelium in gliomas. Lab Invest. 2002;82(3):345–51.PubMedCrossRefGoogle Scholar
  58. 58.
    Ishiwata T, Kudo M, Onda M, Fujii T, Teduka K, Suzuki T, Korc M, Naito Z. Defined localization of nestin-expressing cells in L-arginine-induced acute pancreatitis. Pancreas. 2006;32(4):360–8.PubMedCrossRefGoogle Scholar
  59. 59.
    Oklu R, Walker TG, Wicky S, Hesketh R. Angiogenesis and current antiangiogenic strategies for the treatment of cancer. J Vasc Interv Radiol. 2010;21(12):1791–805.PubMedCrossRefGoogle Scholar
  60. 60.
    Kahan BD, Rapamune USSG. Efficacy of sirolimus compared with azathioprine for reduction of acute renal allograft rejection: a randomised multicentre study. Lancet. 2000;356(9225):194–202.PubMedCrossRefGoogle Scholar
  61. 61.
    Guba M, von Breitenbuch P, Steinbauer M, Koehl G, Flegel S, Hornung M, Bruns CJ, Zuelke C, Farkas S, Anthuber M, Jauch KW, Geissler EK. Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nat Med. 2002;8(2):128–35.PubMedCrossRefGoogle Scholar
  62. 62.
    Kwon YS, Hong HS, Kim JC, Shin JS, Son Y. Inhibitory effect of rapamycin on corneal neovascularization in vitro and in vivo. Invest Ophthalmol Vis Sci. 2005;46(2):454–60.PubMedCrossRefGoogle Scholar
  63. 63.
    Huang S, Bjornsti MA, Houghton PJ. Rapamycins: mechanism of action and cellular resistance. Cancer Biol Ther. 2003;2(3):222–32.PubMedCrossRefGoogle Scholar
  64. 64.
    Saunders RN, Metcalfe MS, Nicholson ML. Rapamycin in transplantation: a review of the evidence. Kidney Int. 2001;59(1):3–16.PubMedCrossRefGoogle Scholar
  65. 65.
    Guertin DA, Sabatini DM. Defining the role of mTOR in cancer. Cancer Cell. 2007;12(1):9–22.PubMedCrossRefGoogle Scholar
  66. 66.
    Law BK. Rapamycin: an anti-cancer immunosuppressant? Crit Rev Oncol Hematol. 2005;56(1):47–60.PubMedCrossRefGoogle Scholar
  67. 67.
    Wienecke R, Fackler I, Linsenmaier U, Mayer K, Licht T, Kretzler M. Antitumoral activity of rapamycin in renal angiomyolipoma associated with tuberous sclerosis complex. Am J Kidney Dis. 2006;48(3):E27–9.PubMedCrossRefGoogle Scholar
  68. 68.
    Herry I, Neukirch C, Debray MP, Mignon F, Crestani B. Dramatic effect of sirolimus on renal angiomyolipomas in a patient with tuberous sclerosis complex. Eur J Intern Med. 2007;18(1):76–7.PubMedCrossRefGoogle Scholar
  69. 69.
    Morton JM, McLean C, Booth SS, Snell GI, Whitford HM. Regression of pulmonary lymphangioleiomyomatosis (PLAM)-associated retroperitoneal angiomyolipoma post-lung transplantation with rapamycin treatment. J Heart Lung Transplant. 2008;27(4):462–5.PubMedCrossRefGoogle Scholar
  70. 70.
    Bissler JJ, McCormack FX, Young LR, Elwing JM, Chuck G, Leonard JM, Schmithorst VJ, Laor T, Brody AS, Bean J, Salisbury S, Franz DN. Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. New Engl J Med. 2008;358(2):140–51.PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Yilmaz R, Akoglu H, Yirkpantur A, Kilickap S, Arici M, Altun B, Aki T, Erdem Y, Yasavul U, Turgan C. A novel immunosuppressive agent, sirolimus, in the treatment of Kaposi’s sarcoma in a renal transplant recipient. Ren Fail. 2007;29(1):103–5.PubMedCrossRefGoogle Scholar
  72. 72.
    Stallone G, Schena A, Infante B, Di Paolo S, Loverre A, Maggio G, Ranieri E, Gesualdo L, Schena FP, Grandaliano G. Sirolimus for Kaposi’s sarcoma in renal-transplant recipients. New Engl J Med. 2005;352(13):1317–23.PubMedCrossRefGoogle Scholar
  73. 73.
    Ormerod AD, Shah SAA, Copeland P, Omar G, Winfield A. Treatment of psoriasis with topical sirolimus: preclinical development and a randomized, double-blind trial. Brit J Dermatol. 2005;152(4):758–64.CrossRefGoogle Scholar
  74. 74.
    Haemel AK, O’Brian AL, Teng JM. Topical rapamycin a novel approach to facial angiofibromas in tuberous sclerosis. Arch Dermatol. 2010;146(7):715–8.PubMedCrossRefGoogle Scholar
  75. 75.
    Choi B, Kang NM, Nelson JS. Laser speckle imaging for monitoring blood flow dynamics in the in vivo rodent dorsal skin fold model. Microvasc Res. 2004;68(2):143–6.PubMedCrossRefGoogle Scholar
  76. 76.
    Tan W, Jia W, Sun V, Mihm MC, Nelson JS. Topical rapamycin suppresses the angiogenesis pathways induced by pulsed dye laser: mechanisms of inhibition of regeneration and revascularization of photocoagulated blood vessels. Laser Surg Med. 2012;44(10):796–804. in press.CrossRefGoogle Scholar
  77. 77.
    Medici D, Olsen BR. Rapamycin inhibits proliferation of hemangioma endothelial cells by reducing HIF-1-dependent expression of VEGF. PLoS One. 2012;7(8):e42913.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Phung TL, Ziv K, Dabydeen D, Eyiah-Mensah G, Riveros M, Perruzzi C, Sun J, Monahan-Earley RA, Shiojima I, Nagy JA, Lin MI, Walsh K, Dvorak AM, Briscoe DM, Neeman M, Sessa WC, Dvorak HF, Benjamin LE. Pathological angiogenesis is induced by sustained Akt signaling and inhibited by rapamycin. Cancer Cell. 2006;10(2):159–70.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Chen H, Xiong T, Qu Y, Zhao F, Ferriero D, Mu D. mTOR activates hypoxia-inducible factor-1alpha and inhibits neuronal apoptosis in the developing rat brain during the early phase after hypoxia-ischemia. Neurosci Lett. 2012;507(2):118–23.PubMedCrossRefGoogle Scholar
  80. 80.
    Sekiguchi Y, Zhang J, Patterson S, Liu L, Hamada C, Tomino Y, Margetts PJ. Rapamycin inhibits transforming growth factor beta induced peritoneal angiogenesis by blocking the secondary hypoxic response. J Cell Mol Med. 2011;16(8):1934–45.CrossRefGoogle Scholar
  81. 81.
    Wang W, Jia WD, Xu GL, Wang ZH, Li JS, Ma JL, Ge YS, Xie SX, Yu JH. Antitumoral activity of rapamycin mediated through inhibition of HIF-1alpha and VEGF in hepatocellular carcinoma. Dig Dis Sci. 2009;54(10):2128–36.PubMedCrossRefGoogle Scholar
  82. 82.
    Vuiblet V, Birembaut P, Francois A, Cordonnier C, Noel LH, Goujon JM, Paraf F, Machet MC, Girardot-Seguin S, Lebranchu Y, Rieu P. Sirolimus-based regimen is associated with decreased expression of glomerular vascular endothelial growth factor. Nephrol Dial Transplant. 2012;27(1):411–6.PubMedCrossRefGoogle Scholar
  83. 83.
    Hudson CC, Liu M, Chiang GG, Otterness DM, Loomis DC, Kaper F, Giaccia AJ, Abraham RT. Regulation of hypoxia-inducible factor 1alpha expression and function by the mammalian target of rapamycin. Mol Cell Biol. 2002;22(20):7004–14.PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Nelson JS, Jia W, Phung TL, Mihm Jr MC. Observations on enhanced port wine stain blanching induced by combined pulsed dye laser and rapamycin administration. Laser Surg Med. 2011;43(10):939–42.CrossRefGoogle Scholar
  85. 85.
    Kilcline C, Frieden IJ. Infantile hemangiomas: how common are they? A systematic review of the medical literature. Pediatr Dermatol. 2008;25(2):168–73.PubMedCrossRefGoogle Scholar
  86. 86.
    Innes FL. Classification of haemangiomata. Br J Plast Surg. 1953;6(2):76–7.PubMedCrossRefGoogle Scholar
  87. 87.
    Lo K, Mihm M, Fay A. Current theories on the pathogenesis of infantile hemangioma. Semin Ophthalmol. 2009;24(3):172–7.PubMedCrossRefGoogle Scholar
  88. 88.
    Yu Y, Flint AF, Mulliken JB, Wu JK, Bischoff J. Endothelial progenitor cells in infantile hemangioma. Blood. 2004;103(4):1373–5.PubMedCrossRefGoogle Scholar
  89. 89.
    Ritter MR, Dorrell MI, Edmonds J, Friedlander SF, Friedlander M. Insulin-like growth factor 2 and potential regulators of hemangioma growth and involution identified by large-scale expression analysis. Proc Natl Acad Sci U S A. 2002;99(11):7455–60.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Razon MJ, Kraling BM, Mulliken JB, Bischoff J. Increased apoptosis coincides with onset of involution in infantile hemangioma. Microcirculation. 1998;5(2–3):189–95.PubMedCrossRefGoogle Scholar
  91. 91.
    Leaute-Labreze C, Prey S, Ezzedine K. Infantile haemangioma: part I. Pathophysiology, epidemiology, clinical features, life cycle and associated structural abnormalities. J Eur Acad Dermatol Venereol. 2011;25(11):1245–53.PubMedCrossRefGoogle Scholar
  92. 92.
    Khan ZA, Boscolo E, Picard A, Psutka S, Melero-Martin JM, Bartch TC, Mulliken JB, Bischoff J. Multipotential stem cells recapitulate human infantile hemangioma in immunodeficient mice. J Clin Invest. 2008;118(7):2592–9.PubMedPubMedCentralGoogle Scholar
  93. 93.
    Chiller KG, Frieden IJ, Arbiser JL. Molecular pathogenesis of vascular anomalies: classification into three categories based upon clinical and biochemical characteristics. Lymphat Res Biol. 2003;1(4):267–81.PubMedCrossRefGoogle Scholar
  94. 94.
    Takahashi K, Mulliken JB, Kozakewich HP, Rogers RA, Folkman J, Ezekowitz RA. Cellular markers that distinguish the phases of hemangioma during infancy and childhood. J Clin Invest. 1994;93(6):2357–64.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Jinnin M, Medici D, Park L, Limaye N, Liu Y, Boscolo E, Bischoff J, Vikkula M, Boye E, Olsen BR. Suppressed NFAT-dependent VEGFR1 expression and constitutive VEGFR2 signaling in infantile hemangioma. Nat Med. 2008;14(11):1236–46.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Wu JK, Adepoju O, De Silva D, Baribault K, Boscolo E, Bischoff J, Kitajewski J. A switch in Notch gene expression parallels stem cell to endothelial transition in infantile hemangioma. Angiogenesis. 2010;13(1):15–23.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Boscolo E, Bischoff J. Vasculogenesis in infantile hemangioma. Angiogenesis. 2009;12(2):197–207.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Boye E, Yu Y, Paranya G, Mulliken JB, Olsen BR, Bischoff J. Clonality and altered behavior of endothelial cells from hemangiomas. J Clin Invest. 2001;107(6):745–52.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Hoeger PH. Infantile haemangioma: new aspects on the pathogenesis of the most common skin tumour in children. Br J Dermatol. 2011;164(2):234–5.PubMedCrossRefGoogle Scholar
  100. 100.
    Uihlein LC, Liang MG, Mulliken JB. Pathogenesis of infantile hemangiomas. Pediatr Ann. 2012;41(8):1–6.PubMedCrossRefGoogle Scholar
  101. 101.
    North PE, Waner M, Mizeracki A, Mihm Jr MC. GLUT1: a newly discovered immunohistochemical marker for juvenile hemangiomas. Hum Pathol. 2000;31(1):11–22.PubMedCrossRefGoogle Scholar
  102. 102.
    North PE, Waner M, Mizeracki A, Mrak RE, Nicholas R, Kincannon J, Suen JY, Mihm Jr MC. A unique microvascular phenotype shared by juvenile hemangiomas and human placenta. Arch Dermatol. 2001;137(5):559–70.PubMedGoogle Scholar
  103. 103.
    Barnes CM, Christison-Lagay EA, Folkman J. The placenta theory and the origin of infantile hemangioma. Lymphat Res Biol. 2007;5(4):245–55.PubMedCrossRefGoogle Scholar
  104. 104.
    Barnes CM, Huang S, Kaipainen A, Sanoudou D, Chen EJ, Eichler GS, Guo Y, Yu Y, Ingber DE, Mulliken JB, Beggs AH, Folkman J, Fishman SJ. Evidence by molecular profiling for a placental origin of infantile hemangioma. Proc Natl Acad Sci U S A. 2005;102(52):19097–102.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Ritter MR, Butschek RA, Friedlander M, Friedlander SF. Pathogenesis of infantile haemangioma: new molecular and cellular insights. Expert Rev Mol Med. 2007;9(32):1–19.PubMedCrossRefGoogle Scholar
  106. 106.
    Garzon MC, Drolet BA, Baselga E, Chamlin SL, Haggstrom AN, Horii K, Lucky AW, Mancini AJ, Metry DW, Newell B, Nopper AJ, Frieden IJ. Comparison of infantile hemangiomas in preterm and term infants: a prospective study. Arch Dermatol. 2008;144(9):1231–2.PubMedCrossRefGoogle Scholar
  107. 107.
    Haggstrom AN, Drolet BA, Baselga E, Chamlin SL, Garzon MC, Horii KA, Lucky AW, Mancini AJ, Metry DW, Newell B, Nopper AJ, Frieden IJ. Prospective study of infantile hemangiomas: demographic, prenatal, and perinatal characteristics. J Pediatr. 2007;150(3):291–4.PubMedCrossRefGoogle Scholar
  108. 108.
    Burton BK, Schulz CJ, Angle B, Burd LI. An increased incidence of haemangiomas in infants born following chorionic villus sampling (CVS). Prenat Diagn. 1995;15(3):209–14.PubMedCrossRefGoogle Scholar
  109. 109.
    Kaplan P, Normandin Jr J, Wilson GN, Plauchu H, Lippman A, Vekemans M. Malformations and minor anomalies in children whose mothers had prenatal diagnosis: comparison between CVS and amniocentesis. Am J Med Genet. 1990;37(3):366–70.PubMedCrossRefGoogle Scholar
  110. 110.
    Pittman KM, Losken HW, Kleinman ME, Marcus JR, Blei F, Gurtner GC, Marchuk DA. No evidence for maternal-fetal microchimerism in infantile hemangioma: a molecular genetic investigation. J Invest Dermatol. 2006;126(11):2533–8.PubMedCrossRefGoogle Scholar
  111. 111.
    Kleinman ME, Blei F, Gurtner GC. Circulating endothelial progenitor cells and vascular anomalies. Lymphat Res Biol. 2005;3(4):234–9.PubMedCrossRefGoogle Scholar
  112. 112.
    Hamlat A, Adn M, Pasqualini E, Brassier G, Askar B. Pathophysiology of capillary haemangioma growth after birth. Med Hypotheses. 2005;64(6):1093–6.PubMedCrossRefGoogle Scholar
  113. 113.
    Colonna V, Resta L, Napoli A, Bonifazi E. Placental hypoxia and neonatal haemangioma: clinical and histological observations. Br J Dermatol. 2010;162(1):208–9.PubMedCrossRefGoogle Scholar
  114. 114.
    Lopez Gutierrez JC, Avila LF, Sosa G, Patron M. Placental anomalies in children with infantile hemangioma. Pediatr Dermatol. 2007;24(4):353–5.PubMedCrossRefGoogle Scholar
  115. 115.
    Ahrens WA, Ridenour 3rd RV, Caron BL, Miller DV, Folpe AL. GLUT-1 expression in mesenchymal tumors: an immunohistochemical study of 247 soft tissue and bone neoplasms. Hum Pathol. 2008;39(10):1519–26.PubMedCrossRefGoogle Scholar
  116. 116.
    Feldser D, Agani F, Iyer NV, Pak B, Ferreira G, Semenza GL. Reciprocal positive regulation of hypoxia-inducible factor 1alpha and insulin-like growth factor 2. Cancer Res. 1999;59(16):3915–8.PubMedGoogle Scholar
  117. 117.
    Herbert A, Ng H, Jessup W, Kockx M, Cartland S, Thomas SR, Hogg PJ, Wargon O. Hypoxia regulates the production and activity of glucose transporter-1 and indoleamine 2,3-dioxygenase in monocyte-derived endothelial-like cells: possible relevance to infantile haemangioma pathogenesis. Br J Dermatol. 2011;164(2):308–15.PubMedCrossRefGoogle Scholar
  118. 118.
    Ritter MR, Reinisch J, Friedlander SF, Friedlander M. Myeloid cells in infantile hemangioma. Am J Pathol. 2006;168(2):621–8.PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Bischoff J. Monoclonal expansion of endothelial cells in hemangioma: an intrinsic defect with extrinsic consequences? Trends Cardiovasc Med. 2002;12(5):220–4.PubMedCrossRefGoogle Scholar
  120. 120.
    Allen RC, Zoghbi HY, Moseley AB, Rosenblatt HM, Belmont JW. Methylation of HpaII and HhaI sites near the polymorphic CAG repeat in the human androgen-receptor gene correlates with X chromosome inactivation. Am J Hum Genet. 1992;51(6):1229–39.PubMedPubMedCentralGoogle Scholar
  121. 121.
    Walter JW, North PE, Waner M, Mizeracki A, Blei F, Walker JW, Reinisch JF, Marchuk DA. Somatic mutation of vascular endothelial growth factor receptors in juvenile hemangioma. Genes Chromosomes Cancer. 2002;33(3):295–303.PubMedCrossRefGoogle Scholar
  122. 122.
    Dadras SS, North PE, Bertoncini J, Mihm MC, Detmar M. Infantile hemangiomas are arrested in an early developmental vascular differentiation state. Mod Pathol. 2004;17(9):1068–79.PubMedCrossRefGoogle Scholar
  123. 123.
    Friedlander SF, Ritter MR, Friedlander M. Recent progress in our understanding of the pathogenesis of infantile hemangiomas. Lymphat Res Biol. 2005;3(4):219–25.PubMedCrossRefGoogle Scholar
  124. 124.
    Ritter MR, Moreno SK, Dorrell MI, Rubens J, Ney J, Friedlander DF, Bergman J, Cunningham BB, Eichenfield L, Reinisch J, Cohen S, Veccione T, Holmes R, Friedlander SF, Friedlander M. Identifying potential regulators of infantile hemangioma progression through large-scale expression analysis: a possible role for the immune system and indoleamine 2,3 dioxygenase (IDO) during involution. Lymphat Res Biol. 2003;1(4):291–9.PubMedCrossRefGoogle Scholar
  125. 125.
    Azzopardi S, Wright TC. Novel strategies for managing infantile hemangiomas: a review. Ann Plast Surg. 2012;68(2):226–8.PubMedCrossRefGoogle Scholar
  126. 126.
    Mabeta P, Pepper MS. Hemangiomas – current therapeutic strategies. Int J Dev Biol. 2011;55(4–5):431–7.PubMedCrossRefGoogle Scholar
  127. 127.
    Ezekowitz RA, Mulliken JB, Folkman J. Interferon alfa-2a therapy for life-threatening hemangiomas of infancy. N Engl J Med. 1992;326(22):1456–63.PubMedCrossRefGoogle Scholar
  128. 128.
    Barlow CF, Priebe CJ, Mulliken JB, Barnes PD, Mac Donald D, Folkman J, Ezekowitz RA. Spastic diplegia as a complication of interferon Alfa-2a treatment of hemangiomas of infancy. J Pediatr. 1998;132(3 Pt 1):527–30.PubMedCrossRefGoogle Scholar
  129. 129.
    Luo QF, Zhao FY. The effects of Bleomycin A5 on infantile maxillofacial haemangioma. Head Face Med. 2011;7:11.PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Leaute-Labreze C, Dumas de la Roque E, Hubiche T, Boralevi F, Thambo JB, Taieb A. Propranolol for severe hemangiomas of infancy. N Engl J Med. 2008;358(24):2649–51.PubMedCrossRefGoogle Scholar
  131. 131.
    Menezes MD, McCarter R, Greene EA, Bauman NM. Status of propranolol for treatment of infantile hemangioma and description of a randomized clinical trial. Ann Otol Rhinol Laryngol. 2011;120(10):686–95.PubMedCrossRefGoogle Scholar
  132. 132.
    Storch CH, Hoeger PH. Propranolol for infantile haemangiomas: insights into the molecular mechanisms of action. Br J Dermatol. 2010;163(2):269–74.PubMedCrossRefGoogle Scholar
  133. 133.
    Greenberger S, Boscolo E, Adini I, Mulliken JB, Bischoff J. Corticosteroid suppression of VEGF-A in infantile hemangioma-derived stem cells. N Engl J Med. 2010;362(11):1005–13.PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Edgerton MT. The treatment of hemangiomas: with special reference to the role of steroid therapy. Ann Surg. 1976;183(5):517–32.PubMedPubMedCentralCrossRefGoogle Scholar
  135. 135.
    Batta K, Goodyear HM, Moss C, Williams HC, Hiller L, Waters R. Randomised controlled study of early pulsed dye laser treatment of uncomplicated childhood haemangiomas: results of a 1-year analysis. Lancet. 2002;360(9332):521–7.PubMedCrossRefGoogle Scholar
  136. 136.
    Admani S, Krakowski AC, Nelson JS, Eichenfield LF, Friedlander SF. Beneficial effects of early pulsed dye laser therapy in individuals with infantile hemangiomas. Dermatol Surg. 2012;38(10):1732–8.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag London Ltd. 2017

Authors and Affiliations

  • Wangcun Jia
    • 1
  • Carol Cheng
    • 2
  • Wenbin Tan
    • 1
  • Martin C. MihmJr
    • 2
  • J. Stuart Nelson
    • 1
    • 3
  1. 1.Beckman Laser Institute, Department of SurgeryUniversity of CaliforniaIrvineUSA
  2. 2.Department of DermatologyBrigham and Women’s Hospital, Harvard Institute of MedicineBostonUSA
  3. 3.Department of Biomedical EngineeringUniversity of CaliforniaIrvineUSA

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