Does hypoxia play a role in infantile hemangioma?

Abstract

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.

Dieulafoy lesions and PHACE syndrome

“…If this was the case, the 5‐year delay for these lesions to become symptomatic could be consistent with the age of first occurrence of DLs reported in the literature . Another potential explanation is the development of DLs in the context of localized hypoxia secondary to regional anomalous vascular development . And finally, the use of rapamycin and/or prolonged (3 years) antiangiogenic, multimodality treatment potentially altered the natural involution process of IHs with “rebound” angiogenesis.…”

“…3 Another potential explanation is the development of DLs in the context of localized hypoxia secondary to regional anomalous vascular development. 15,16 And finally, the use of rapamycin and/or prolonged (3 years) antiangiogenic, multimodality…”

Infantile hemangiomas with minimal or arrested growth: A retrospective case series

“…The distribution of segmental IH of the extremities seems to follow patterns related to arterial supply. It is hypothesized that IH develops in response to local tissue or systemic hypoxia in an attempt at revascularization . Reimer et al hypothesized that variant arterial anatomy during embryo‐fetal development might contribute to temporary regional hypoxia, thus stimulating angiogenesis resulting in IH.…”

“…It is hypothesized that IH develops in response to local tissue or systemic hypoxia in an attempt at revascularization. 11,13 Reimer et al 12 hypothesized that variant arterial anatomy during embryo-fetal development might contribute to temporary regional hypoxia, thus stimulating angiogenesis resulting in IH. Moreover, the embryologic delay regarding the formation of leg buds compared to arm buds might explain the higher prevalence of IH-MAG on the lower extremities.…”

Association of ATF4 Expression With Tissue Hypoxia and M2 Macrophage Infiltration in Infantile Hemangioma

“…7 Both previous studies and physical manifestations have indicated the presence of hypoxic condition and its promotive role in IH. 8,9 However, the precise mechanism accounting for hypoxia-mediated IH progression has not been fully clarified. Therefore, it is essential to discover novel molecular events underlying this process, which may provide better insights into the biological course of IH.…”