Downregulation Of Lysyl Oxidase In Venous Malformations: Association With Vascular Destabilization And Sclerotherapy

Objective:Venous malformations were a slow-flow,non-proliferative vascular malformations characterized by irregular dilatation of the venous lumen,reduced perivascular cell coverage,which indicating vascular destabilization.As an enzyme that regulates extracellular matrix deposition,lysyl oxidase(LOX)plays an important role in vascular development and disease.The purpose of this study was to investigate the potential role of lysyl oxidase in the pathogenesis of venous malformation and to evaluate its significance in venous malformation sclerotherapy.Methods:The expression of lysyl oxidase(LOX)were detected by immunohistochemistry in normal skin tissues and venous malformations,and the correlation between LOX and the expression of perivascular cells markerα-SMA/the expression of TGF-βwas analyzed by Spearman rank correlation test.The correlation of LOX expression with vascular destabilization was analyzed by serial sections,double-labeling immunofluorescence.The in vitro studies were carried out for exploring the underlying mechanisms by western blot and real-time quantitative PCR.Human umbilical vein endothelial cells(HUVEC)were treated with bleomycin,the exogenous cytokine TGF-βand the inhibitor of LOX,β-aminopropanitrile(BAPN).Results:LOX expression in venous malformation was significantly down-regulated compared with normal skin tissue,and was significantly positively correlated with perivascularα-SMA~+cell coverage and TGF-βexpression.In vitro data demonstrated that both recombinant TGF-βand bleomycin induced obvious up-regulation of LOX expression and activity and a concomitant increase in extracellular matrix(ECM)components in HUVECs,which could be reversed by LOX inhibition.Conclusions:LOX expression was significantly decreased in venous malformation,which is closely related to vascular destabilization and TGF-β‐induced endothelial ECM deposition.In addition,LOX is involved in the sclerotherapy of venous malformations and is expected to be a therapeutic target for venous malformations.