Search

Port wine stain (PWS) is a congenital vascular malformation of human skin involving the superficial vascular plexus,1-4 but the molecular pathogenesis of these lesions remains incompletely understood.5-8 We herein performed a transmission electron microscopy (TEM) study to determine the main pathological characteristics and ultrastructure of various cell types, including endothelial cells (ECs), pericytes, fibroblasts and keratinocytes, in hypertrophic and nodular PWS. The study was approved by the Investigational Review Board at the Xijing Hospital, Xi'an, China. This article is protected by copyright. All rights reserved.

Author(s): Tan, W; Zakka, LR; Gao, L; Wang, J; Zhou, F; Selig, MK; Anvari, R; Sukanthanag, A; Wang, G; Mihm, MC; Nelson, JS

Port-wine stain (PWS) is a congenital, progressive vascular malformation of human skin involving the superficial vascular plexus. PWS occurs in an estimated 3–5 children per 1000 live births.1–3 In childhood, PWSs are flat red macules, but lesions tend to darken progressively to purple and, by middle age, often become raised as a result of the development of vascular nodules.4,5 Recently, a low-frequency allelic mutation (c.548G→A, p.R183Q) in the guanine nucleotide-binding protein G alpha subunit q has been identified in PWS skin.6 We have also found consecutive activation of c-Jun N-terminal kinases and extracellular signal regulated kinases (ERKs) in both infantile and adult PWS.7 Taken together, these studies have begun to elucidate the molecular mechanisms underlying the pathogenesis of PWS. Pulsed dye laser (PDL) is the current treatment of choice for PWS.8,9 However, if the ultimate standard required is complete blanching of the lesion, the degree of PWS blanching achieved following PDL can be variable and unpredictable, with an average treatment success rate below 10% owing to blood vessel recurrence.10–12 The regeneration and revascularization of blood vessels post-PDL treatment is a critical barrier that must be overcome in order to achieve an adequate PWS therapeutic outcome.13 Recent data suggest that activation of angiogenesis pathways induced by PDL in PWS contributes to this process.13 Thus, we hypothesize that a better PWS therapeutic outcome might be achieved with PDL combined with the administration of anti-angiogenesis agents. In our previous studies, we have demonstrated that topical rapamycin (RPM) can suppress the PDL-induced angiogenesis in rodent skin and that systemic administration of RPM post-PDL enhances the blanching response in patients with PWS.13,14 However, multiple signalling pathways are generally activated during PDL-induced angiogenesis; thus, a multitarget inhibitor, such as axitinib, may produce a better anti-angiogenesis effect than RPM, which mainly blocks the protein kinase B (AKT)/mammalian target of rapamycin (mTOR)/ribosomal protein S6 kinase (P70S6K) pathway.15,16 Axitinib, a U.S. Food and Drugs Administration-approved anti-angiogenesis agent for the second-line treatment of patients with advanced renal cell carcinoma, can inhibit many angiogenic tyrosine kinases, including vascular endothelial growth factor (VEGF) receptors (VEGFRs) 1–3, platelet-derived growth factor receptor and stem cell growth factor receptor.17 In this study, we attempted to combine PDL with topical administration of axitinib in order to evaluate its effectiveness in suppressing PDL-induced angiogenesis in rodent skin.