Abstract: Objective To study the protective effects of dopamine D₄ receptors on high glucose-induced injury in vascular endothelial cells and the possible mechanisms involved. Methods After streptozotocin（STZ）-induced rat diabetic model was established,Western blot was used to detect the changes in the expression of D₄ receptors.Human umbilical vein endothelial cells（HUVEC）in vitro culture were used as target cells. After treated by high glucose（33mmol/L）,the HUVEC viability and the changes of D₄ receptors were detected. HUVEC were treated by high glucose in presence or absence of D₄ receptor agonist PD168077（10-7 mol/L）,phosphatidylinositol 3-kinase（PI3K）inhibitor LY294002（5×10-5 mol/L）and endothelial nitric oxide synthase（eNOS）inhibitor l-NAME（10-4 mol/L）and then the cell viability was determined. Phosphorylated protein kinase B（Akt）and eNOS levels and total Akt and eNOS levels were detected respectively. Results The expression of D₄ receptors decreased significantly in thoracic aortas endothelium in diabetic rats and HUVEC（both P＜0.05）. In high glucose condition,HUVEC viability deceased. Compared with high glucose group,HUVEC’viability was increased in the presence of PD168077（P＜0.05）. In addition,in presence of LY294002 and l-NAME,HUVEC viability was deceased in this process（P＜0.05）. At the same time,Akt phosphorylationhigh glucose+LY294002+PD168077group（0.59±0.09）,high glucose+l-NAME+PD168077group（0.62±0.07）,high glucose+PD168077group（1.44±0.07）,P＜0.05and eNOS phosphorylationhigh glucose+LY294002+PD168077group（0.62±0.05）,high glucose+l-NAME+PD168077group（0.66±0.08）,high glucose+PD168077group（1.44±0.08）,P＜0.05levels were deceased after PI3 Kand eNOS activities were blocked. Conclusion Dopamine D₄ receptors can ameliorate high glucose-induced HUVEC injury,which is probably related to PI3K/Akt/eNOS pathway.