In the present study, we found that in our large animal model of chronic myocardial ischemia, intramyocardial injection of hypoxia-modified EVs, when compared to normoxia serum-starved EVs, is associated with (1) improved cardiac contractility as measured by dP/dtmax and Lw derived from the PRSW relationship, (2) increased capillary density in ischemic myocardial tissue with trends towards improved perfusion, (3) increased proangiogenic signaling markers including Akt, ERK1/2, and VE-Cadherin, and (4) decreased anti-angiogenic signaling markers endostatin and angiostatin. Here, MAPK3 is linked to myocardial ischemia.