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Published on: June 11, 2017
Expression of (pro)renin receptor and its effect on endothelial cell proliferation in infantile hemangioma
Bede van Schaijik1, Swee T Tan2,3, Reginald W Marsh1,4
1Gillies McIndoe Research Institute, Wellington, New Zealand.
Insights
Renin activates the (pro)renin receptor (PRR) to promote infantile hemangioma (IH) cell proliferation via the wnt signaling pathway. This finding offers a new therapeutic target for IH treatment.
Area of Science:
- Vascular Biology
- Oncology
- Endocrinology
Background:
- Infantile hemangioma (IH) proliferation is linked to the renin-angiotensin system (RAS).
- The (pro)renin receptor (PRR) is a key RAS component involved in wnt signaling.
- PRR activation by renin is hypothesized to drive IH growth.
Purpose of the Study:
- To investigate the expression and role of PRR in infantile hemangioma.
- To determine if renin directly stimulates IH cell proliferation.
- To elucidate the signaling pathway involved in renin-induced IH growth.
Main Methods:
- Immunohistochemical (IHC) staining and NanoString analysis to assess PRR expression in IH tissues and cells.
- MTT assay to evaluate the effect of renin on IH cell viability.
- RT-qPCR to analyze stem cell gene expression.
- Utilized wnt receptor blocker dickkopf-1 to assess pathway involvement.
Main Results:
- PRR was confirmed to be expressed at both transcriptional and translational levels in IH endothelial and non-endothelial cells.
- Renin administration significantly increased the number of viable IH cells.
- The proliferative effect of renin was blocked by dickkopf-1, indicating wnt pathway activation.
Conclusions:
- Renin-induced PRR activation promotes IH cell proliferation through the wnt signaling pathway.
- This mechanism may explain cell accumulation during the proliferative phase of IH.
- Targeting the renin-PRR-wnt axis presents a potential therapeutic strategy for problematic IH.
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.
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