Genetic lineage tracing reveals poor angiogenic potential of cardiac endothelial cells

AIMS: Cardiac ischemia does not elicit an efficient angiogenic response. Indeed, lack of surgical revascularization upon myocardial infarction results in cardiomyocyte death, scarring and loss of contractile function. Clinical trials aimed at inducing therapeutic revascularization through the delivery of pro-angiogenic molecules after cardiac ischemia have invariably failed, suggesting that endothelial cells in the heart cannot mount an efficient angiogenic response. To understand why the heart is a poorly angiogenic environment, here we compare the angiogenic response of the cardiac and skeletal muscle using a lineage tracing approach to genetically label sprouting endothelial cells. METHODS AND RESULTS: We observed that overexpression of the Vascular Endothelial Growth Factor in the skeletal muscle potently stimulated angiogenesis, resulting in the formation of a massive number of new capillaries and arterioles. In contrast, response to the same dose of the same factor in the heart was blunted and consisted in a modest increase in the number of new arterioles. By using Apelin-CreER mice to genetically label sprouting endothelial cells we observed that different pro-angiogenic stimuli activated Apelin expression in both muscle types to a similar extent, however only in the skeletal muscle these cells were able to sprout, form elongated vascular tubes activating Notch signaling, and became incorporated into arteries. In the heart, Apelin-positive cells transiently persisted and failed to give rise to new vessels. When we implanted cancer cells in different organs, the abortive angiogenic response in the heart resulted in a reduced expansion of the tumor mass. CONCLUSION: Our genetic lineage tracing indicates that cardiac endothelial cells activate Apelin expression in response to pro-angiogenic stimuli but, different from those of the skeletal muscle, fail to proliferate and form mature and structured vessels. The poor angiogenic potential of the heart is associated with reduced tumor angiogenesis and growth of cancer cells. TRANSLATIONAL PERSPECTIVE: Cardiac ischemia is a leading cause of morbidity and mortality worldwide. Various clinical trials have attempted to revascularize ischemic hearts through the delivery of pro-angiogenic molecules, but they have invariably failed.Our results indicate that cardiac endothelial cells sense pro-angiogenic stimuli but are not able to drive an efficient angiogenic response. This poor angiogenic potential is also associated with reduced growth of cancer cells in the heart.This work provides some mechanisms behind the poor angiogenic capacity of the heart and paves the way to future strategies for the therapy of both cancer and cardiac ischemia.