European Journal of Pediatrics

, Volume 171, Issue 6, pp 941–946 | Cite as

Urinary matrix metalloproteinases-2/9 in healthy infants and haemangioma patients prior to and during propranolol therapy

  • C. J. Kleber
  • A. Spiess
  • J. B. Kleber
  • U. Hinz
  • S. Holland-Cunz
  • J. Weiss
Original Article


The mechanism of therapeutic success of propranolol for severe infantile haemangioma remains unclear. Propranolol was shown to modify matrix metalloproteinase (MMP) levels, which are associated with tumour pathogenesis. We hypothesized that urinary MMP2/9 is higher in patients with infantile haemangioma compared to healthy infants and that propranolol reduces MMP2/9 levels and thus leads to an involution of the haemangioma. In this case, MMP2/9 could be used as a marker of indicated therapy or therapeutic success. Urinary samples were taken before, 2 weeks after, and 2 months after the beginning of propranolol treatment in haemangioma patients and once in healthy controls. Activity of MMP2/9 was determined by commercially available activity kits. Urine of 22 haemangioma patients and 21 control subjects was obtained. Propranolol therapy had significant success in all patients. MMP2/9 was present in most samples, the younger the children the higher the MMP2 levels. Haemangioma patients showed lower levels of MMP2. The MMP2 levels were significantly higher after 2 weeks of propranolol than prior to therapy. There were no differences in MMP9 levels. Conclusions: Presence of MMP2/9 in the urine of infants <1 year can be explained by high rate of physiological tissue remodelling. Unexpectedly, MMP2 was lower in the urine of haemangioma patients and higher 2 weeks after propranolol treatment. Taking this and the diverse results in literature into account, the correlation between MMPs, proliferation, and regression of haemangiomas and propranolol remains unclear.


Haemangioma Propranolol Matrix metalloproteinases 



The study was funded by the Heidelberg Foundation of Surgery. We thank the paediatric offices of Dr. Wiens and Drs. Scheffzek and Greiner for their kind help with sample collection.

Conflict of interest

No conflicts of interest for any author. No financial relationship of any author with the Heidelberg Foundation of Surgery.


  1. 1.
    Annabi B, Lachambre MP, Plouffe K, Moumdjian R, Béliveau R (2009) Propranolol adrenergic blockage inihibits human brain endothelial cells tubulogenesis and matrix metalloproteinase-9 secretion. Pharmacol Res 60:438–445PubMedCrossRefGoogle Scholar
  2. 2.
    Berg JN, Walter JW, Thisanagayam U, Evans M, Blei F, Waner M, Diamond AG, Marchuk DA, Porteous ME (2001) Evidence for loss of heterozygosity of 5q in sporadic haemangiomas: are somatic mutations involved in haemangioma formation? J Clin Pathol 54:249–252PubMedCrossRefGoogle Scholar
  3. 3.
    Bielenberg DR, Bucana CD, Sanchez R, Mulliken JB, Folkman J, Fidler IJ (1999) Progressive growth of infantile cutaneous haemangiomas is directly correlated with hyperplasia and angiogenesis of adjacent epidermis and inversely correlated with expression of endogenous angiogenesis inhibitor, IFN-beta. Int J Oncol 14:401–408PubMedGoogle Scholar
  4. 4.
    Boye E, Yu Y, Paranya G, Mulliken J, Olsen B, Bischoff J (2001) Clonality and altered behavior of endothelial cells from haemangiomas. J Clin Invest 107:745–752PubMedCrossRefGoogle Scholar
  5. 5.
    Calicchio ML, Collins T, Kozakewich HP (2009) Identification of signaling systems in proliferating and involuting phase infantile haemangiomas by genome-wide transcriptional profiling. Am J Pathol 174:1638–1649PubMedCrossRefGoogle Scholar
  6. 6.
    Dadras SS, North PE, Bertoncini J, Mihm MC, Detmar M (2004) Infantile haemangiomas are arrested in an early developmental vascular differentiation state. Mod Pathol 17:1068–1079PubMedCrossRefGoogle Scholar
  7. 7.
    Demers M, Couillard J, Bélanger S, St-Pierre Y (2005) New roles for matrix metalloproteinases in metastasis. Crit Rev Immunol 25:493–523PubMedGoogle Scholar
  8. 8.
    Fischer T (2004) Design und Synthese von Matrix Metalloproteinase Inhibitoren mit 1,2,4-Triazin-Grundgerüst. Doctoral Thesis. Bielefeld, GermanyGoogle Scholar
  9. 9.
    Guo D, Kassiri Z, Basu R, Chow FL, Kandalam V, Damilano F, Liang W, Izumo S, Hirsch E, Penninger JM, Backx PH, Oudit GY (2010) Loss of PI3K{gamma} enhances cAMP-dependent MMP remodelling of the myocardial N-cadherin adhesion complexes and extracellular matrix in response to early biomechanical stress. Circ Res 107:1275–1289PubMedCrossRefGoogle Scholar
  10. 10.
    Hajighasemi F, Hajighasemi S (2009) Effect of propranolol on angiogenic factors in human hematopoietic cell lines in vitro. Iran Biomed J 13:223–228PubMedGoogle Scholar
  11. 11.
    Khan ZA, Melero-Martin JM, Wu X, Paruchuri S, Boscolo E, Mulliken JB, Bischoff J (2006) Endothelial progenitor cells from infantile haemangioma and umbilical cord blood display unique cellular responses to endostatin. Blood 108:915–921PubMedCrossRefGoogle Scholar
  12. 12.
    Kleinman ME, Greives MR, Churgin SS, Blechman KM, Chang EI, Ceradini DJ, Tepper OM, Gurtner GC (2007) Hypoxia-induced mediators of stem/progenitor cell trafficking are increased in children with haemangioma. Arterioscler Thromb Vasc Biol 27:2664–2670PubMedCrossRefGoogle Scholar
  13. 13.
    Lamoreaux WJ, Fitzgerald MEC, Reiner A, Hasty KA, Charles ST (1998) Vascular endothelial growth factor increases release of gelatinase A and decreases release of tissue inhibitor of metalloproteinases by microvascular endothelial cells in vitro. Microvasc Res 55:29–42PubMedCrossRefGoogle Scholar
  14. 14.
    Lamy S, Lachambre MP, Lord-Dufour S, Béliveau R (2009) Propranolol suppresses angiogenesis in vitro: inhibition of proliferation, migration, and differentiation of endothelial cells. Vascul Pharmacol 53:200–208CrossRefGoogle Scholar
  15. 15.
    Léauté-Labrèze C, Dumas de la Roque E, Hubiche T, Boralevi F, Thambo JB, Taïeb A (2008) Propranolol for severe haemangiomas of infancy. N Engl J Med 358:2649–2651PubMedCrossRefGoogle Scholar
  16. 16.
    Marler JJ, Fishman SJ, Kilroy SM, Fang J, Upton J, Mulliken JB, Burrows PE, Zurakowski D, Folkman J, Moses MA (2005) Increased expression of urinary matrix metalloproteinases parallels the extent and activity of vascular anomalies. Pediatrics 116:38–45PubMedCrossRefGoogle Scholar
  17. 17.
    Nagase H, Visse R, Murphy G (2006) Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc Res 69:562–573PubMedCrossRefGoogle Scholar
  18. 18.
    Romana-Souza B, Nascimento AP, Monte-Alto-Costa A (2008) Low-dose propranolol improves cutaneous wound healing of burn-injured rats. Plast Reconstr Surg 122:1690–1699PubMedCrossRefGoogle Scholar
  19. 19.
    Romana-Souza B, Ortranto M, Viera AM, Filgueiras CC, Fierro IM, Monte-Alto-Costa A (2010) Rotational stress-induced increase in epinephrine levels delays cutaneous wound healing in mice. Brain Behav Immun 24:427–437PubMedCrossRefGoogle Scholar
  20. 20.
    Storch CH, Hoeger PH (2010) Propranolol for infantile haemangiomas: insights into the molecular mechanisms of action. Br J Dermatol 163:269–274PubMedCrossRefGoogle Scholar
  21. 21.
    Tallant C, Marrero A, Gomis-Rüth FX (2010) Matrix metalloproteinases: fold and function of their catalytic domains. Biochim Biophys Acta 1803:20–28PubMedCrossRefGoogle Scholar
  22. 22.
    Thrailkill KM, Kumar S, Rosenberg CK, Auten KJ, Fowlkes JL (1999) Characterization of matrix metalloproteinases in human urine: alterations during adolescence. Pediatr Nephrol 13:223–229PubMedCrossRefGoogle Scholar
  23. 23.
    Visse R, Nagase H (2003) Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ Res 92:827–839PubMedCrossRefGoogle Scholar
  24. 24.
    Willenberg T, Baumgartner I (2008) Vascular birthmarks. Vasa 37:5–17PubMedCrossRefGoogle Scholar
  25. 25.
    Yu Y, Flint AF, Mulliken JB, Wu JK, Bischoff J (2004) Endothelial progenitor cells in infantile haemangioma. Blood 103:1373–1375PubMedCrossRefGoogle Scholar
  26. 26.
    Zhong S, Yang G, Xia C, Zhang D, Shan S (2009) Expression of matrix metalloproteinase and its tissue inhibitor in haemangioma. J Huazhong Univ Sci Technol 29:614–619CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • C. J. Kleber
    • 1
  • A. Spiess
    • 1
    • 2
  • J. B. Kleber
    • 3
  • U. Hinz
    • 4
  • S. Holland-Cunz
    • 1
  • J. Weiss
    • 2
  1. 1.Devision of Paediatric SurgeryUniversity Hospital HeidelbergHeidelbergGermany
  2. 2.Department of Clinical Pharmacology and PharmacoepidemiologyUniversity Hospital HeidelbergHeidelbergGermany
  3. 3.Devision of Paediatric CardiologyUniversity Hospital HeidelbergHeidelbergGermany
  4. 4.Department of General, Visceral and Transplantation Surgery Unit for Documentation and StatisticsUniversity Hospital HeidelbergHeidelbergGermany

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