Angiogenesis plays an important role in the pathogenesis of cardiovascular disease. Pro-angiogenic and anti-angiogenic treatments have provided new insights into the impact of angiogenesis-based approaches on coronary artery disease. We have recently reported that the hearts of late pregnant (LP) mice are more prone to ischemia/reperfusion (I/R) injury compared to non pregnant(NP) mice. Provided the significant change of angiogenesis status in pregnancy, here we explored whether stimulating the angiogenesis with VEGF is able to protect the heart against I/R injury in late pregnancy, and whether anti-antigenic treatment with soluble endoglin(sENG), an anti-angiogenic factor, aggravates cardiac I/R injury in NP. Pregnant mice at day 12 either received daily injection of VEGF (100 ug/kg daily subcutaneous injection) or PBS(LP CTRL) for 7 days, and at day 19 the LP mice hearts were subjected to 20 min ischemia followed by 40 min reperfusion in Langendorff. NP mice either received a single adenovirus sENG(2х10 8particles via tail vein injection) or vehicle(NP CTRL), and 10 days later NP mice were subjected to 20 min ischemia followed by 40 min reperfusion in Langendorff. The heart function was recorded throughout the experiments, and the infarct size was measured by TTC staining at the end of experiments. Exogenous VEGF treatment significantly improved the cardiac function of LP mice after ischemia. The rate pressure product (RPP) at the end of reperfusion was improved from 1617±287 mmHg*beats/min (n=6) in LP CTRL to 11287±1783 mmHg*beats/min (n=3) in the VEGF group(p<0.01). The infarct size was also significantly reduced by VEGF treatment to 25.0±4.3% (n=3) from 57.4±5.2%(n=6) in CTRL (p<0.01). While sENG aggravated the cardiac I/R injury in NP, as the RPP at the end of reperfusion in the sENG group (4523±1281 mmHg*beats/min, n=4) was significantly lower compared with NP CTRL group(12818±1213 mmHg*beats/min, n=6)(p<0.01). Furthermore, the infarct size in the sENG group was markedly higher compared with NP CTRL group (34.0±3.3% (n=4) vs. 16.3±1.4%(n=6) in NP CTRL, p<0.05). In conclusion, anti-angiogenic treatment aggravates the cardiac I/R injury in NP, while angiogenic therapy protects the heart against I/R injury in LP.