Aim The proliferation of endothelial cells plays an important role in angiogenesis.In present study,we observed the effect of syndecan-4 on human umbilical vein endothelial cells(HUVECs) proliferation as well as its possible mechanism. Methods HUVECs were isolated and cultured.The cells were infected with Ad-syndecan-4 or Ad-null as control.Immunostaining was performed to investigate syndecan-4 expression and clusterization.Western blotting was used to assess phosphorylation of downstream kinase Akt and endothelial nitric oxide synthase(eNOS).Proliferation ability of HUVECs was assessed by p-H3,bromodeoxyuridine(5-BrdU) and 5-ethynyl-2′-deoxyuridine(EdU). Results Compared with the Ad-null group,increased cell proliferation rate was observed in the Ad-syndecan-4 group.Syndecan-4 overexpression induced the clusterization of syndecan-4 themselves.The levels of Akt and eNOS phosphorylation were also increased in HUVECs with syndecan-4 overexpression. Conclusion Overexpressed syndecan-4 induced the self-clusterization of syndecan-4 and the activation of downstream Akt and eNOS,which may contribute to increased proliferation of HUVECs.