Abnormal alterations in cardiac expression of vascular endothelial growth factor (VEGF) as well as its receptors and impairment in the development of coronary collaterals have recently been reported in diabetic subjects. However, the presence of pharmacological intervention on these defects in diabetes remains unsettled. Here, we studied the effect of endothelin (ET) receptor blockade on cardiac VEGF signaling pathways and cardiac function in Sprague-Dawley rats 5 weeks after induction of Type I diabetes with streptozotocin (65 mg/kg, i.p.) in comparison with age-matched control rats. One week after streptozotocin, some diabetic rats were treated with the ET receptor antagonist SB209670 (1 mg/day) for 4 weeks. VEGF, its receptors, and its angiogenic signaling molecules (phosphorylated Akt and endothelial nitric-oxide synthase [eNOS]) were analyzed by Western blot, enzyme-linked immunosorbent assay, real-time polymerase chain reaction, and immunohistochemistry, and cardiac function was evaluated by echocardiography. Coronary capillary morphology was assessed by lectin and enzymatic double staining. We found significant decreases in cardiac expression of VEGF, its receptors, phosphorylation of Akt and eNOS, and coronary capillary density in diabetic rats as compared with controls. Treatment of diabetic rats with SB209670 reversed these alterations to the control levels and ameliorated impairment of cardiac function. From a molecular point of view, the present study is the first to indicate the potential usefulness of an ET receptor antagonist in the treatment of cardiac dysfunction in Type I diabetes.