Abstract
Background
Propranolol is the preferred treatment for problematic proliferating infantile hemangioma (IH) by targeting the renin–angiotensin system (RAS) expressed by IH endothelium. (Pro)renin receptor (PRR) is a major component of the RAS associated with the canonical wnt signaling pathway. We proposed that activation of PRR by renin causes proliferation of IH.
Methods
The expression of PRR in IH tissue samples was investigated using immunohistochemical (IHC) staining and NanoString analysis. NanoString analysis was also used to confirm transcriptional expression of PRR in CD34-sorted proliferating IH-derived primary cell lines. MTT assay was utilized to determine the effect of exogenous renin on the number of viable IH cells. RT-qPCR was used to determine the effect of renin on the stem cell gene expression.
Results
NanoString analysis and IHC staining confirmed transcriptional and translational expression of PRR, which was localized to the non-endothelial and the endothelial IH cell populations. MTT assay demonstrated an increased number of viable IH cells by administration of renin and the effect was negated by the wnt receptor blocker dickkopf-1.
Conclusion
Our results present a model for renin-induced increased proliferation of IH cells through PRR acting via the wnt signaling pathway, which may account for accumulation of cells in IH during the proliferative phase of the tumor.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Itinteang, T., Brasch, H. D., Tan, S. T. & Day, D. J. Expression of components of the renin-angiotensin system in proliferating infantile haemangioma may account for the propranolol-induced accelerated involution. J. Plast. Reconstr. Aesthet. Surg. 64, 759–765 (2011).
Tan, S. T. et al. A novel in vitro human model of hemangioma. Mod. Pathol. 13, 92–99 (2000).
North, P. E. et al. A unique microvascular phenotype shared by juvenile hemangiomas and human placenta. Arch. Dermatol 137, 559–570 (2001).
Takahashi, K. et al. Cellular markers that distinguish the phases of hemangioma during infancy and childhood. J. Clin. Invest 93, 2357–2364 (1994).
Itinteang, T. et al. Infantile haemangioma expresses embryonic stem cell markers. J. Clin. Pathol. 65, 394–398 (2012).
Harbi, S. et al. Infantile hemangioma originates from a dysregulated but not fully transformed multipotent Stem Cell. Sci. Rep. 6, 35811 (2016).
Itinteang, T., Tan, S. T., Brasch, H. & Day, D. J. Primitive mesodermal cells with a neural crest stem cell phenotype predominate proliferating infantile haemangioma. J. Clin. Pathol. 63, 771–776 (2010).
Khan, Z. A. et al. Multipotential stem cells recapitulate human infantile hemangioma in immunodeficient mice. J. Clin. Invest 118, 2592–2599 (2008).
Huang, L., Nakayama, H., Klagsbrun, M., Mulliken, J. B. & Bischoff, J. Glucose transporter 1-positive endothelial cells in infantile hemangioma exhibit features of facultative stem cells. Stem Cells 33, 133–145 (2015).
Ritter, M. R., Reinisch, J., Friedlander, S. F. & Friedlander, M. Myeloid cells in infantile hemangioma. Am. J. Pathol. 168, 621–628 (2006).
Dornhoffer, J. R., Wei, T., Zhang, H., Miller, E., MA, C. & Richter, G. T. The expression of renin-angiotensin-aldosterone axis components in infantile hemangioma tissue and the impact of propranolol treatment. Pediatr. Res 82, 155–163 (2017).
Nguyen, G. et al. Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin. J. Clin. Invest. 109, 1417–1427 (2002).
Griendling, K. K., Murphy, T. J. & Alexander, R. W. Molecular biology of the renin-angiotensin system. Circulation 87, 1816–1828 (1993).
Satofuka, S. et al. Pro)renin receptor promotes choroidal neovascularization by activating its signal transduction and tissue renin-angiotensin system. Am. J. Pathol. 173, 1911–1918 (2008).
Balakumar, P. & Jagadeesh, G. Potential cross-talk between (pro)renin receptors and Wnt/frizzled receptors in cardiovascular and renal disorders. Hypertens. Res. 34, 1161–1170 (2011).
MacDonald, B. T., Tamai, K. & He, X. Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev. Cell 17, 9–26 (2009).
Niida, A. et al. DKK1, a negative regulator of Wnt signaling, is a target of the beta-catenin/TCF pathway. Oncogene 23, 8520–8526 (2004).
Cruciat, C. M. et al. Requirement of prorenin receptor and vacuolar H + -ATPase-mediated acidification for Wnt signaling. Science 327, 459–463 (2010).
Liu, F. Y., Liu, X. Y., Zhang, L. J., Cheng, Y. P. & Jiang, Y. N. Binding of prorenin to (pro)renin receptor induces the proliferation of human umbilical artery smooth muscle cells via ROS generation and ERK1/2 activation. J. Renin Angiotensin Aldosterone Syst. 15, 99–108 (2014).
Yisireyili, M. et al. Indoxyl sulfate-induced activation of (pro)renin receptor promotes cell proliferation and tissue factor expression in vascular smooth muscle cells. PLoS ONE 9, e109268 (2014).
Uraoka, M. et al. Prorenin induces ERK activation in endothelial cells to enhance neovascularization independently of the renin-angiotensin system. Biochem. Biophys. Res. Commun. 390, 1202–1207 (2009).
van Schaijik, B., Davis, P. F., Wickremesekera, A. C., Tan, S. T. & Itinteang, T. Subcellular localisation of the stem cell markers OCT4, SOX2, NANOG, KLF4 and c-MYC in cancer: a review. J. Clin. Pathol. 71, 88–91 (2018).
Ram, R. S. et al. Cancer stem cells in moderately differentiated lip squamous cell carcinoma express components of the renin-angiotensin system. Front Surg. 4, 30 (2017).
Koh, S. P. et al. Embryonic stem cell-like population in Dupuytren’s disease. Plast. Reconstr. Surg. Glob. Open 4, e1064 (2016).
Narita, T. et al. Placental (pro)renin receptor expression and plasma soluble (pro)renin receptor levels in preeclampsia. Placenta 37, 72–78 (2016).
Itinteang, T., Marsh, R., Davis, P. F. & Tan, S. T. Angiotensin II causes cellular proliferation in infantile haemangioma via angiotensin II receptor 2 activation. J. Clin. Pathol. 68, 346–350 (2015).
Tan, C. E., Itinteang, T., Leadbitter, P., Marsh, R. & Tan, S. T. Low-dose propranolol regimen for infantile haemangioma. J. Paediatr. Child Health 51, 419–424 (2015).
Tan, S. T. et al. Treatment of infantile haemangioma with captopril. Br. J. Dermatol 167, 619–624 (2012).
Itinteang, T., Withers, A. H., Davis, P. F. & Tan, S. T. Biology of infantile hemangioma. Front Surg. 1, 38 (2014).
Christodoulides, C. et al. The Wnt antagonist Dickkopf-1 and its receptors are coordinately regulated during early human adipogenesis. J. Cell Sci. 119, 2613–2620 (2006).
Acknowledgements
We thank Ms. Liz Jones and Dr. Helen Brasch of the Gillies McIndoe Research Institute for their assistance in IHC staining and the diagnosis of IH and interpretation of the DAB IHC results. No external funding was secured for this project.
Author information
Authors and Affiliations
Contributions
T.I. formulated the hypothesis. T.I., S.T.T., and B.v.S. designed the study. T.I. and S.T.T. interpreted the IHC and NanoString data. B.v.S., S.T.T., and T.I. interpreted the cell culture and RT-PCR data. R.M. carried out the statistical analysis. B.v.S., T.I., and S.T.T. drafted the paper. All authors approved the paper.
Corresponding author
Ethics declarations
Competing interests
T.I. and S.T. are inventors of a provisional patent Treatment of Vascular Anomalies (PCT/NZ2017/050032). The remaining authors declare no competing interest.
Additional information
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Rights and permissions
About this article
Cite this article
van Schaijik, B., Tan, S.T., Marsh, R.W. et al. Expression of (pro)renin receptor and its effect on endothelial cell proliferation in infantile hemangioma. Pediatr Res 86, 202–207 (2019). https://doi.org/10.1038/s41390-019-0430-8
Received:
Accepted:
Published:
Version of record:
Issue date:
DOI: https://doi.org/10.1038/s41390-019-0430-8
This article is cited by
-
Targeting the (pro)renin receptor in cancers: from signaling to pathophysiological effects
Journal of Cancer Research and Clinical Oncology (2023)
