Infantile hemangioma (IH), the most common tumor of infancy, is characterized by an initial proliferation during infancy followed by spontaneous involution over the next 5–10 years, often leaving a fibro-fatty residuum. IH is traditionally considered a tumor of the microvasculature. However, recent data show the critical role of stem cells in the biology of IH with emerging evidence suggesting an embryonic developmental anomaly due to aberrant proliferation and differentiation of a hemogenic endothelium with a neural crest phenotype that possesses the capacity for endothelial, hematopoietic, mesenchymal, and neuronal differentiation. Current evidence suggests a putative placental chorionic mesenchymal core cell embolic origin of IH during the first trimester. This review outlines the emerging role of stem cells and their interplay with the cytokine niche that promotes a post-natal environment conducive for vasculogenesis involving VEGFR-2 and its ligand VEGF-A and the IGF-2 ligand in promoting cellular proliferation, and the TRAIL-OPG anti-apoptotic pathway in preventing cellular apoptosis in IH. The discovery of the role of the renin–angiotensin system in the biology of IH provides a plausible explanation for the programed biologic behavior and the β-blocker-induced accelerated involution of this enigmatic condition. This crucially involves the vasoactive peptide, angiotensin II, that promotes cellular proliferation in IH predominantly via its action on the ATIIR2 isoform. The role of the RAS in the biology of IH is further supported by the effect of captopril, an ACE inhibitor, in inducing accelerated involution of IH. The discovery of the critical role of RAS in IH represents a novel and fascinating paradigm shift in the understanding of human development, IH, and other tumors in general.

Infantile hemangioma (IH), the most common tumor of infancy, is characterized by rapid growth during infancy, followed by spontaneous involution over 5-10 years. Certain clinical observations have led to the suggestion that IH is triggered and maintained by hypoxia. We review the literature on the possible role of hypoxia in the etiology of IH, in particular, (1) the role of hypoxia inducible factor-1α (HIF-1α) and its downstream targets including GLUT-1 and VEGF; (2) the pathophysiological link between IH and retinopathy of prematurity; (3) hypoxic events in the early life including placental insufficiency, pre-eclampsia and low birthweight that have the potential to promote hypoxic stress; and (4) the evidence supporting the development of IH independent of HIF-1α. We also discuss these observations in the context of recent evidence of the crucial role of stem cells and the cytokines niche that governs their proliferation and inevitable differentiation, offering novel insights into the biology of IH. We propose that various triggers may simultaneously up-regulate HIF-1α, which is downstream of the renin-angiotensin system, specifically angiotensin II, which promotes production of HIF-1α. These developments shed light to the understanding of this enigmatic condition.

The recent discovery of the crucial role of stem cells and the inferred role of the renin-angiotensin system in the biology of infantile hemangioma underscores the possibility of even more targeted therapies, by using modulators of the renin-angiotensin system, on infantile hemangioma. The observation of the potential role of these traditional antihypertensive agents in stem cell biology may lead to better understanding of developmental biology and tumor stem cell growth.