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Mouse Bone Marrow-Derived Endothelial Progenitor Cells Do Not Restore Radiation-Induced Microvascular Damage

DOI: 10.1155/2014/506348

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Background. Radiotherapy is commonly used to treat breast and thoracic cancers but it also causes delayed microvascular damage and increases the risk of cardiac mortality. Endothelial cell proliferation and revascularization are crucial to restore microvasculature damage and maintain function of the irradiated heart. We have therefore examined the potential of bone marrow-derived endothelial progenitor cells (BM-derived EPCs) for restoration of radiation-induced microvascular damage. Material & Methods. 16?Gy was delivered to the heart of adult C57BL/6 mice. Mice were injected with BM-derived EPCs, obtained from Eng+/+ or Eng+/? mice, 16 weeks and 28 weeks after irradiation. Morphological damage was evaluated at 40 weeks in transplanted mice, relative to radiation only and age-matched controls. Results. Cardiac irradiation decreased microvascular density and increased endothelial damage in surviving capillaries (decrease alkaline phosphatase expression and increased von Willebrand factor). Microvascular damage was not diminished by treatment with BM-derived EPCs. However, BM-derived EPCs from both Eng+/+ and Eng+/? mice diminished radiation-induced collagen deposition. Conclusion. Treatment with BM-derived EPCs did not restore radiation-induced microvascular damage but it did inhibit fibrosis. Endoglin deficiency did not impair this process. 1. Introduction Radiotherapy is commonly used for treatment of thoracic and chest wall tumors. Although radiotherapy is effective against the cancer, it is also known to induce delayed damage in surrounded normal tissue, including cardiac damage [1–4]. Nowadays, the volume of the heart exposed to radiation is kept as low as possible but for most left sided breast cancer patients the heart still receives a treatment dose of 1 to 5?Gy and this can eventually lead to ischemic heart disease [2, 5–8]. Preclinical studies have demonstrated the involvement of radiation-induced microvascular damage in the development of cardiac injury. Radiation leads to endothelial cell loss, which results in a decrease in microvascular density. Radiation also activates thrombotic and inflammatory reactions in the remaining vessels and induces the development of fibrosis in the myocardium [9–12]. Perfusion defects, measured with single photon emission computerized tomography (SPECT), have been identified in asymptomatic breast cancer patients 6 to 18 months after radiotherapy. The incidence of perfusion defects is much higher for patients with left sided cancer (71%), where radiation dose to the heart is higher, than for right sided cancer


[1]  B. M. Aleman, A. W. van den Belt-Dusebout, M. L. de Bruin et al., “Late cardiotoxicity after treatment for Hodgkin lymphoma,” Blood, vol. 109, no. 5, pp. 1878–1886, 2007.
[2]  S. C. Darby, M. Ewertz, and P. Hall, “Omalizumab for chronic urticaria,” The New England Journal of Medicine, vol. 368, no. 26, pp. 2527–2530, 2013.
[3]  G. Gyenes, L. E. Rutqvist, A. Liedberg, and T. Fornander, “Long-term cardiac morbidity and mortality in a randomized trial of pre- and postoperative radiation therapy versus surgery alone in primary breast cancer,” Radiotherapy & Oncology, vol. 48, no. 2, pp. 185–190, 1998.
[4]  P. McGale, S. C. Darby, P. Hall et al., “Incidence of heart disease in 35,000 women treated with radiotherapy for breast cancer in Denmark and Sweden,” Radiotherapy & Oncology, vol. 100, no. 2, pp. 167–175, 2011.
[5]  M. C. Aznar, S.-S. Korreman, A. N. Pedersen, G. F. Persson, M. Josipovic, and L. Specht, “Evaluation of dose to cardiac structures during breast irradiation,” The British Journal of Radiology, vol. 84, no. 1004, pp. 743–746, 2011.
[6]  R. Jagsi, J. Moran, R. Marsh, K. Masi, K. A. Griffith, and L. J. Pierce, “Evaluation of four techniques using intensity-modulated radiation therapy for comprehensive locoregional irradiation of breast cancer,” International Journal of Radiation Oncology Biology Physics, vol. 78, no. 5, pp. 1594–1603, 2010.
[7]  F. Lohr, M. El-Haddad, B. Dobler et al., “Potential effect of robust and simple IMRT approach for left-sided breast cancer on cardiac mortality,” International Journal of Radiation Oncology Biology Physics, vol. 74, no. 1, pp. 73–80, 2009.
[8]  L. K. Schubert, V. Gondi, E. Sengbusch et al., “Dosimetric comparison of left-sided whole breast irradiation with 3DCRT, forward-planned IMRT, inverse-planned IMRT, helical tomotherapy, and topotherapy,” Radiotherapy & Oncology, vol. 100, no. 2, pp. 241–246, 2011.
[9]  M. Boerma, J. J. Kruse, M. M. van Loenen et al., “Increased deposition of von Willebrand factor in the rat heart after local ionizing irradiation,” Strahlentherapie und Onkologie, vol. 180, no. 2, pp. 109–116, 2004.
[10]  K. Gabriels, S. Hoving, I. Seemann, N. L. Visser, M. J. Gijbels, et al., “Local heart irradiation of ApoE?/? mice induces microvascular and endocardial damage and accelerates coronary atherosclerosis,” Radiotherapy & Oncology, vol. 105, no. 3, pp. 358–364, 2012.
[11]  I. Seemann, K. Gabriels, N. L. Visser et al., “Irradiation induced modest changes in murine cardiac function despite progressive structural damage to the myocardium and microvasculature,” Radiotherapy & Oncology, vol. 103, no. 2, pp. 143–150, 2012.
[12]  S. Schultz-Hector and K. Balz, “Radiation-induced loss of endothelial alkaline phosphatase activity and development of myocardial degeneration: an ultrastructural study,” Laboratory Investigation, vol. 71, no. 2, pp. 252–260, 1994.
[13]  L. B. Marks, X. Yu, R. G. Prosnitz et al., “The incidence and functional consequences of RT-associated cardiac perfusion defects,” International Journal of Radiation Oncology Biology Physics, vol. 63, no. 1, pp. 214–223, 2005.
[14]  B. Seddon, A. Cook, L. Gothard et al., “Detection of defects in myocardial perfusion imaging in patients with early breast cancer treated with radiotherapy,” Radiotherapy & Oncology, vol. 64, no. 1, pp. 53–63, 2002.
[15]  J. M. Isner and T. Asahara, “Angiogenesis and vasculogenesis as therapeutic strategies for postnatal neovascularization,” The Journal of Clinical Investigation, vol. 103, no. 9, pp. 1231–1236, 1999.
[16]  T. Takahashi, C. Kalka, H. Masuda et al., “Ischemia- and cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization,” Nature Medicine, vol. 5, no. 4, pp. 434–438, 1999.
[17]  B. Vailhé, D. Vittet, and J.-J. Feige, “In vitro models of vasculogenesis and angiogenesis,” Laboratory Investigation, vol. 81, no. 4, pp. 439–452, 2001.
[18]  D. W. Losordo and S. Dimmeler, “Therapeutic angiogenesis and vasculogenesis for ischemic disease. Part II: cell-based therapies,” Circulation, vol. 109, no. 22, pp. 2692–2697, 2004.
[19]  C. Urbich, C. Heeschen, A. Aicher, E. Dernbach, A. M. Zeiher, and S. Dimmeler, “Relevance of monocytic features for neovascularization capacity of circulating endothelial progenitor cells,” Circulation, vol. 108, no. 20, pp. 2511–2516, 2003.
[20]  T. Asahara, H. Masuda, T. Takahashi et al., “Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization,” Circulation Research, vol. 85, no. 3, pp. 221–228, 1999.
[21]  S. A. Abdalla and M. Letarte, “Hereditary haemorrhagic telangiectasia: current views on genetics and mechanisms of disease,” Journal of Medical Genetics, vol. 43, no. 2, pp. 97–110, 2006.
[22]  S. van den Driesche, C. L. Mummery, and C. J. Westermann, “Hereditary hemorrhagic telangiectasia: an update on transforming growth factor β signaling in vasculogenesis and angiogenesis,” Cardiovascular Research, vol. 58, no. 1, pp. 20–31, 2003.
[23]  H. M. Arthur, J. Ure, A. J. Smith et al., “Endoglin, an ancillary TGFβ receptor, is required for extraembryonic angiogenesis and plays a key role in heart development,” Developmental Biology, vol. 217, no. 1, pp. 42–53, 2000.
[24]  A. Bourdeau, D. J. Dumont, and M. Letarte, “A murine model of hereditary hemorrhagic telangiectasia,” The Journal of Clinical Investigation, vol. 104, no. 10, pp. 1343–1351, 1999.
[25]  S. Post, A. M. Smits, A. J. van den Broek et al., “Impaired recruitment of HHT-1 mononuclear cells to the ischaemic heart is due to an altered CXCR4/CD26 balance,” Cardiovascular Research, vol. 85, no. 3, pp. 494–502, 2010.
[26]  F. Lebrin and C. L. Mummery, “Endoglin-mediated vascular remodeling: mechanisms underlying hereditary hemorrhagic telangiectasia,” Trends in Cardiovascular Medicine, vol. 18, no. 1, pp. 25–32, 2008.
[27]  K. A. Hinds, J. M. Hill, E. M. Shapiro et al., “Highly efficient endosomal labeling of progenitor and stem cells with large magnetic particles allows magnetic resonance imaging of single cells,” Blood, vol. 102, no. 3, pp. 867–872, 2003.
[28]  Y. Cheng, S. Guo, G. Liu, Y. Feng, B. Yan, et al., “Transplantation of bone marrow-derived endothelial progenitor cells attenuates myocardial interstitial fibrosis and cardiac dysfunction in streptozotocin-induced diabetic rats,” International Journal of Molecular Medicine, vol. 30, no. 4, pp. 870–876, 2012.
[29]  H. Sekiguchi, M. Ii, K. Jujo, A. Yokoyama, N. Hagiwara, and T. Asahara, “Improved culture-based isolation of differentiating endothelial progenitor cells from mouse bone marrow mononuclear cells,” PLoS ONE, vol. 6, no. 12, Article ID e28639, 2011.
[30]  R. W. Qi, H. W. Bao, H. H. Yan, G. Dai, M. L. Wei, and Q. Yan, “Purification and growth of endothelial progenitor cells from murine bone marrow mononuclear cells,” Journal of Cellular Biochemistry, vol. 103, no. 1, pp. 21–29, 2008.


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