Decreased levels of VEGF, a key angiogenic factor, is known to lead to inadequate collateral formation in hearts of diabetic (DM) animal models and patients. However, prevention of VEGF decrease and its therapeutic potential in DM hearts, has not been studied. The present study investigated whether endothelin (ET)-A/B dual receptor antagonist (SB209670, 1 mg/rat/day) would reverse the down regulation of VEGF signaling in early streptozotocin (STZ)-induced diabetic hearts of male rats. Rats were administeredcitrate saline (vehicle) or STZ (65 mg/kg IP). Diabetes was confirmedby hyperglycemia and after1 week of diabetes, animals were separated into those receiving SB209670, or vehicle for 4 weeks. Levels of VEGF in DM heart were significantly decreased (7.8±1, pg/mg) than in non-DM rats (12±1.3, pg/mg), and SB209670 treatment prevented VEGF down regulation in DM hearts (13.0±3.8 pg/mg). Moreover, ET antagonism restored to normal levels of signaling molecules down stream of VEGF, namely phosphorylated Akt and eNOS in DM heart. ET antagonism also prevented development of mild cardiac function impairment in DM rats, as revealed by echocardiography, and improved the decreased coronary capillary density. However, the treatment had no effect on higher plasma glucose or lower insulin level in DM rats. This study is the first to demonstrate a potential therapeutic option in the preservation of myocardial microvasculature in DM and prevention of the associated DM cardiac complications. Supported by Ministry of Education and Science in Japan.