Pigment epithelium‐derived factor/vascular endothelial growth factor ratio plays a crucial role in the spontaneous regression of infant hemangioma and in the therapeutic effect of propranolol

Abstract

Infantile hemangioma (IH) is a benign tumor that is formed by aberrant angiogenesis and that undergoes spontaneous regression over time. Propranolol, the first‐line therapy for IH, inhibits angiogenesis by downregulating activation of the vascular endothelial growth factor (VEGF) pathway, which is hyperactivated in IH. However, this treatment is reportedly ineffective for 10% of tumors, and 19% of patients relapse after propranolol treatment. Both pro‐angiogenic and anti‐angiogenic factors regulate angiogenesis, and pigment epithelium‐derived factor (PEDF) is the most effective endogenous anti‐angiogenic factor. PEDF/VEGF ratio controls many angiogenic processes, but its role in IH and the relationship between this ratio and propranolol remain unknown. Results of the present study showed that the PEDF/VEGF ratio increased during the involuting phase of IH compared with the proliferating phase. Similarly, in hemangioma‐derived endothelial cells (HemEC), which were isolated with magnetic beads, increasing the PEDF/VEGF ratio inhibited proliferation, migration, and tube formation and promoted apoptosis. Mechanistically, the VEGF receptors (VEGFR1 and VEGFR2) and PEDF receptor (laminin receptor, LR) were highly expressed in both IH tissues and HemEC, and PEDF inhibited HemEC function by binding to LR. Interestingly, we found that propranolol increased the PEDF/VEGF ratio but did so by lowering VEGF expression rather than by upregulating PEDF as expected. Furthermore, the combination of PEDF and propranolol had a more suppressive effect on HemEC. Consequently, our results suggested that the PEDF/VEGF ratio played a pivotal role in the spontaneous regression of IH and that the combination of PEDF and propranolol might be a promising treatment strategy for propranolol‐resistant IH.

Itraconazole Oral Solution for a Case of Infantile Hemangioma: Monitoring the Efficacy by Dermoscopy and MRI

“…IH usually forms within the first week after birth and grows rapidly during the first 3-6 months, known as the proliferating phase of IH. Subsequently, spontaneous regression occurs from 12 months to 5 years of age and beyond [5][6][7]. IH may require intervention owing to serious cosmetic and functional problems.…”

Pigment Epithelium-Derived Factor Promotes the Growth and Migration of Human Esophageal Squamous Cell Carcinoma

“…On the other hand, PEDF is a key regulatory factor in endothelial cells. Angiogenesis is inhibited by PEDF via cleaving VEGFR1 and VEGFR2 at the transmembrane region and VEGF-induced phosphorylation (30).…”

Signalling through cerebral cavernous malformation protein networks

“…Notably, atorvastatin is part of an enrolling phase I/II clinical trial [174]. The anti-VEGF-A antibody bevacizumab [175] and the β-adrenergic blocker and anti-angiogenic agent propranolol are among the few clinical trial candidates [176,177]. While the majority of pharmacological approaches have been rationally designed, recent unbiased small-molecule suppression screens may also hold promise.…”