Hypoxia, Hormones, and Endothelial Progenitor Cells in Hemangioma

Abstract

Hemangiomas are the most common tumor of infancy, and although the natural history of these lesions is well described, their etiology remains unknown. One current theory attributes the development of hemangiomas to placentally-derived cells; however, conclusive evidence to support a placental origin is lacking. While placental tissue and hemangiomas do share molecular similarities, it is possible that these parallels are the result of analogous responses of endothelial cells and vascular progenitors to similar environmental cues. Specifically, both tissue types consist of actively proliferating cells that exist within a low oxygen, high estrogen environment. The hypoxic environment leads to an upregulation of hypoxia inducible factor-1alpha (HIF-1alpha) responsive chemokines such as stromal cell derived factor-1alpha (SDF-1alpha) and vascular endothelial growth factor (VEGF), both of which are known to promote the recruitment and proliferation of endothelial progenitor cells. Increased hormone levels in the postpartum period further potentiate the growth of these lesions. In this model, increased stabilization of HIF-1 in concert with increased levels of estrogen create a milieu that promotes new blood vessel development, ultimately contributing to the pathogenesis of infantile hemangiomas.

Serum concentrations of VEGF and bFGF in the course of propranolol therapy of infantile hemangioma in children: Are we closer to understand the mechanism of action of propranolol on hemangiomas?

“…The drug was discontinued within 1.5-3 months, with gradual reduction of the dose. 10,11 According to those studies, hypoxia increases the expression of hypoxia-inducible factor 1-alpha (HIF-1-alpha), which increases vascular endothelial growth factor A (VEGF-A) production by the non-oxidized endothelial cells. Both hypoxia and stromal cell-derived factor 1-alpha (SDF-1 alpha) increase the differentiation and proliferation of endothelial progenitor cells, leading to the development of hemangioma.…”

“…Both hypoxia and stromal cell-derived factor 1-alpha (SDF-1 alpha) increase the differentiation and proliferation of endothelial progenitor cells, leading to the development of hemangioma. 10,11 Hypoxia is probably the strongest factor inducing angiogenesis and the formation of hemangioma. Multiple pregnancy, alcohol consumption, nicotinism, drug use during pregnancy, shortening of the pregnancy, low birth weight, and consequently poor general condition of the newborn are risk factors for IH and may be associated with increased tissue hypoxia.…”

Oxymatrine suppresses proliferation and induces apoptosis of hemangioma cells through inhibition of HIF-1a signaling

“…11,12 Proliferating HAs express known mediators of vasculogenesis such as HIF-1a and VEGF, which are involved in the initiation or progression of Has. 13 Activation of HIF-2 alpha and consequent overexpression of VEGF by the endothelial cells is involved in the pathogenesis of Has.…”

Refractive and structural changes in infantile periocular capillary haemangioma treated with propranolol

“…Accordingly, capillary haemangiomas are composed of endothelial cells, mast cells, macrophages, and cellular factors such as the angiogenesis-related receptor E-selectin intergrins, aVb3 and a5b1, and basic fibroblast growth factor (bFGF). 9,10 The proliferative phase is characterised by elevated levels of vascular endothelial growth factor and insulin-like growth factor 2, which promote lesion growth from existing vessels. 11,12 The vasculogenesis pathway is implicated by findings that the early endothelial structures and the cellular part of these structures originate from mesoderm-derived haemangioblasts that function as progenitors for haematopoietic and endothelial cells.…”