Coexistence of Eph receptor B1 and ephrin B2 in port-wine stain endothelial progenitor cells contributes to clinicopathological vasculature dilatation

BackgroundPort-wine stain (PWS) is a vascular malformation characterized by progressive dilatation of postcapillary venules, but the molecular pathogenesis remains obscure. ObjectivesTo illustrate that PWS endothelial cells (ECs) present a unique molecular phenotype that leads to pathoanatomical PWS vasculatures. MethodsImmunohistochemistry and transmission electron microscopy were used to characterize the ultrastructure and molecular phenotypes of PWS blood vessels. Primary culture of human dermal microvascular endothelial cells and in vitro tube formation assay were used for confirmative functional studies. ResultsMultiple clinicopathological features of PWS blood vessels during the development and progression of the disease were shown. There were no normal arterioles and venules observed phenotypically and morphologically in PWS skin; arterioles and venules both showed differentiation impairments, resulting in a reduction of arteriole-like vasculatures and defects in capillary loop formation in PWS lesions. PWS ECs showed stemness properties with expression of endothelial progenitor cell markers CD133 and CD166 in non-nodular lesions. They also expressed dual venous/arterial identities, Eph receptor B1 (EphB1) and ephrin B2 (EfnB2). Co-expression of EphB1 and EfnB2 in normal human dermal microvascular ECs led to the formation of PWS-like vasculatures in vitro, for example larger-diameter and thick-walled capillaries. ConclusionsPWS ECs are differentiation-impaired, late-stage endothelial progenitor cells with a specific phenotype of CD133(+)/CD166(+)/EphB1(+)/EfnB2(+), which form immature venule-like pathoanatomical vasculatures. The disruption of normal EC-EC interactions by coexistence of EphB1 and EfnB2 contributes to progressive dilatation of PWS vasculatures. What's already known about this topic? Port-wine stain (PWS) is a congenital progressive vascular malformation of human skin. Vascular lesions are considered as dilation of postcapillary venules in PWS. Pathological alterations involving the entire physiological milieu of skin are present in the early stage of PWS. What does this study add? PWS endothelial cells (ECs) are differentiation-impaired, late-stage endothelial progenitor cells (EPCs) with a phenotype of CD133(+)/CD166(+)/Eph receptor B1 (EphB1)(+)/ephrin B2 (EfnB2)(+). PWS blood vessels are immature venule-like pathoanatomical vasculatures. Coexistence of EphB1 and EfnB2 in PWS ECs contributes to the progressive dilatation of PWS vasculatures. What is the translational message? PWS EPCs are the major contributor to the angiogenesis of PWS blood vessels after pulsed-dye laser therapy. The surface markers EphB1, EfnB2, CD133 and CD166 provide a molecular basis for specific targeting of PWS EPCs. Blockage of EphB1/EfnB2 signalling may promote PWS EPC differentiation and inhibit progressive dilatation of PWS vasculatures. Linked Comment: Fear. Br J Dermatol 2017; 177:1478-1479. Respond to this article