Genetic lineage tracing reveals poor angiogenic potential of cardiac endothelial cells

Abstract

Aims Cardiac ischaemia 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 ischaemia 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 signalling, 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 tumour 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 tumour angiogenesis and growth of cancer cells.

Coronary vessel formation in development and disease: mechanisms and insights for therapy

“…4). These findings were recently supported by a genetic lineage tracing study showing that VEGFA overexpression in the (uninjured) myocardium was sensed by CECs, as demonstrated by apelin expression, however, in contrast to ECs of skeletal muscle, CECs failed to induce downstream angiogenesis 111 . Similarly, the angiogenic enhancer:LacZ constructs coud be ectopically activated by VEGFA injection in other adult tissues, and indeed were still active in remote regions of the MI heart.…”

VEGF-B Promotes Endocardium-Derived Coronary Vessel Development and Cardiac Regeneration

“…This is because an excess of VEGF-B works merely by binding to the VEGFR-1 decoy receptor, thereby displacing the endogenous VEGF for induction of angiogenesis through the VEGFR-2-signaling pathway, which in turn promotes mild CMC growth through paracrine EC-CMC crosstalk 48 . It is important to note, that the therapeutic dosing window is much smaller for VEGF-A than for VEGF-B, because VEGF-A is poorly angiogenic in the heart 49 , and its side effects, such as vascular leakage and inflammation are greater, which thus far has compromised its use in the treatment of cardiovascular ischemic conditions 21,22,50 .…”

Unique Angiogenesis From Cardiac Arterioles During Pericardial Adhesion Formation

“…Evidence of the generation of new blood vessels with αSMApositive cells coverage in myocardial tissues has been recently reported, and αSMA-positive arterioles were discovered in newly formed vascular networks (26). αSMA-positive arterioles were also observed in skeletal muscles and heart tissues of mice with adeno-associated virus-mediated VEGF overexpression (27). The authors reported that VEGF-induced formation of new arterioles in the heart occurred to a lesser extent than in skeletal muscle.…”