Provided herein are compositions and methods for preventing, ameliorating, and/or reducing tissue ischemia and/or tissue damage due to ischemia, increasing blood vessel diameter, blood flow and tissue perfusion in the presence of vascular disease including peripheral vascular disease, atherosclerotic vascular disease, coronary artery disease, stroke and influencing other conditions, by suppressing CD47 and/or blocking TSP1 and/or CD47 activity or interaction. Influencing the interaction of CD47-TSP1 in blood vessels allows for control of blood vessel diameter and blood flow, and permits modification of blood pressure and cardiac function. Under conditions of decreased blood flow, for instance through injury or atherosclerosis, blocking TSP1-CD47 interaction allows blood vessels to dilate and increases blood flow, tissue perfusion and tissue survival. This in turn reduces or prevents tissue necrosis and death. The therapeutics identified herein allow for precise regulation of blood flow to tissues and organs which need it, while substantially avoiding systemic complications. Methods and compositions described herein can be used to increase tissue survival under conditions of trauma and surgery, as well as conditions of chronic vascular disease. Also disclosed are methods for the treatment of elderly subjects using agents that affect TSP1 and CD47 and thereby affect tissue perfusion. Additionally, provided herein are compositions and methods for influencing blood coagulation, allowing for controlled increased or decreased blood clotting. Additionally, provided herein are compositions and methods for decreasing blood flow, as in the case of cancer through mimicking the effects of TSP1 and CD47 on blood vessel diameter and blood flow.