In this project, begun in September 1985, we have been trying to extend the findings that heparin and certain non-anticoagulant heparin fragments can promote the angiogenesis produced in the chick chorioallantoic membrane and in the rabbit cornea by tumor fragments or purified growth factors. That such an affect would occur with systemic administration is not at all certain because the heparin administration in the other bioassays was administered by direct extravascular administration so that the heparin was present along a concentration gradient in the extracellular space and was not first exposed to the plasma and the endothelial cells lining the vascular lumen. Heparin had previously been shown by other workers to promote endothelial cell migration if present in a gradient. We, and others, have shown that heparin binds to endothelium. In addition, heparin binds proteins present in the plasma. Most importantly, however, it is still not established that myocardial ischemia results in angiogenesis as discussed in another annual report. As described in this abstract, we have found that in rats made increasingly ischemic-by graded doses of isoproterenol designed to produce ischemia without infarction-heparin and certain nonanticoagulant tetrasaccharide fragments produced a beneficial effect: a reduction in mortality and myocardial infarct size after left anterior descending coronary artery ligation 24 hours after cessation of the isoproterenol and the heparin (or saline). The usual effects of heparin such as its anticoagulant action appear not the account for this beneficial effect as indicating in the abstract. To confirm directly that this is an angiogenic effect we are counting capillary density and capillary/myocyte ratios in these hearts and quantifying endothelial DNS synthesis by tritiated thymidine autoradiography.
