Infantile hemangioma: the common and enigmatic vascular tumor
Annegret Holm, … , John B. Mulliken, Joyce Bischoff
Annegret Holm, … , John B. Mulliken, Joyce Bischoff
Published April 15, 2024
Citation Information: J Clin Invest. 2024;134(8):e172836. https://doi.org/10.1172/JCI172836.
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Review Series

Infantile hemangioma: the common and enigmatic vascular tumor

Abstract

Infantile hemangioma (IH) is a benign vascular tumor that occurs in 5% of newborns. The tumor follows a life cycle of rapid proliferation in infancy, followed by slow involution in childhood. This unique life cycle has attracted the interest of basic and clinical scientists alike as a paradigm for vasculogenesis, angiogenesis, and vascular regression. Unanswered questions persist about the genetic and molecular drivers of the proliferating and involuting phases. The beta blocker propranolol usually accelerates regression of problematic IHs, yet its mechanism of action on vascular proliferation and differentiation is unclear. Some IHs fail to respond to beta blockers and regrow after discontinuation. Side effects occur and long-term sequelae of propranolol treatment are unknown. This poses clinical challenges and raises novel questions about the mechanisms of vascular overgrowth in IH.

Authors

Annegret Holm, John B. Mulliken, Joyce Bischoff

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Figure 2

Propranolol targets the endothelial transcription factor SOX18 to inhibit vasculogenesis in IH.

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Propranolol targets the endothelial transcription factor SOX18 to inhibi...
(A) The R(+) enantiomers of propranolol and atenolol and the small-molecule SOX18 inhibitor Sm4 inhibit hemangioma stem cell (HemSC) to hemangioma endothelial cell (HemEC) differentiation in vitro and ability of HemSCs to form de novo vessels in vivo. R(+) propranolol inhibits SOX18 by interfering with its search patterns along chromatin, its homodimer (SOX18:SOX18) or heterodimer formation with RBPJ (SOX18:RBPJ), and its transcriptional activation of target genes. In patient tissue, SOX18 expression (magenta) coincides with nuclei (blue) and colocalizes with UEA (gray), indicating its presence in endothelial cells of proliferating IH tissue. The inset confocal image was acquired with a Zeiss LSM 880 by AH. Scale bar: 10 μm. Adapted with permission from the Journal of Clinical Investigation (86). (B) Summary of differential drug mechanisms of action inhibiting IH vasculogenesis. Corticosteroids inhibit the expression of VEGF-A; sirolimus reduces stemness and self-renewal of HemSC; R(+) propranolol and R(+) atenolol act on SOX18 as described in A. SOX18 expression increases over the course of HemSC to HemEC differentiation.