Although the exact pathogenesis of hemangiomas is not completely

understood, histopathologic and cell surface marker studies have improved our
understanding of this entity. Genetic factors have been investigated, with twin
studies suggesting that heredity does not play a large role. This is consistent
with observations that IH usually occur sporadically. Others, however, have
speculated a genetic contribution as evidenced by a doubling of risk if present in
a family member,17 while the racial predilection in Caucasians compared to
non-whites also suggests some genetic component.
Examination of molecular markers expressed by in vivo IH cells, cultured
IH endothelial cells (HemEC), and hemangioma-derived stem cells (HemSC)
have shed considerable light on possible mechanisms. Both angiogenesis (i.e.,
proliferation or migration from preexisting vessels) and vasculogenesis (i.e., de
novo formation of vessels from progenitor cells) have been implicated in the
pathogenesis of IH. In vivo IH cells express endothelial cell and immature
vascular markers.18 Further study of expression patterns of cultured IH
endothelial cells (HemEC) have discovered upregulated glucose transporter
protein type-1 (GLUT-1), vascular endothelial growth factor (VEGF), basic
fibroblast growth factor (bFGF), among others, with downregulation of other
markers, such as CD146.2,17 GLUT-1 is a particularly useful cell surface
marker in the diagnosis of these lesions as they are found exclusively in IH.19
This research on HemEC expression patterns suggests a clonal proliferation of

partially differentiated, immature vascular cells, implicating angiogenesis in the

formation of IH.
More recently, however, attention has turned toward angioproliferative signaling
molecules such as VEGF, a key molecule in vessel formation and likely a
fundamental part of IH formation. Increased serum VEGF-A levels have been
noted in patients with proliferating IH compared to involuting IH as well as
negative controls.20 Similarly, stem cells isolated from human IH demonstrate
VEGF-A expression in the proliferating phase but not in the involuting phase of
IH. This finding was further examined in the setting of the traditional
therapeutic agent of choice, corticosteroids. In vivo mouse studies showed that
dexamethasone treatment blocked secretion of VEGF-A from IH-derived stem
cells.21 Related work provides evidence for a possible mechanism related to
steroid inhibition of NF-B, a molecule associated with both inflammation as
well as angiogenesis.22 Additionally, HemSC have been shown to be capable of
forming functional vessels with an IH-like phenotype without additional
mesenchymal support that is required by other cell populations.23
Cumulatively, this implicates HemSC in vasculogenic formation of IH.
Research investigating the cellular origin of the hematopoietic IH stem cells
points to a population of hematopoietic stem cells called endothelial progenitor
cells (EPCs). This is supported by findings of increased EPCs in peripheral
blood of IH patients, EPC-associated markers localized to endothelium of

proliferating IH, and markers associated with primitive hematopoietic cells

found in forming capillary endothelium.24 However, earlier studies implicate a
possible placental origin based on research demonstrating cross-similarities in
hemangioma endothelial cell and placental cellular markers.25,26
Ultimately, there is much still to be understood about the molecular
pathogenesis of IH; however, the recent advances described above offer new
targets for future therapies, most notably the VEGF cascade.