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Updated: Dec 29, 2025
In Vitro Model of Coronary Angiogenesis
Published on: March 10, 2020
Genetic lineage tracing reveals poor angiogenic potential of cardiac endothelial cells
Tea Kocijan1, Michael Rehman1, Andrea Colliva1
1Cardiovascular Biology Laboratory, International Centre for Genetic Engineering and Biotechnology (ICGEB), Padriciano, 99, 34149 Trieste, Italy.
Insights
Cardiac ischemia impairs blood vessel formation. Unlike skeletal muscle, heart endothelial cells fail to sprout and form new vessels, hindering recovery and tumor growth.
Area of Science:
- Cardiovascular Biology
- Angiogenesis Research
- Muscle Physiology
Background:
- Cardiac ischemia leads to heart damage due to inefficient blood vessel repair.
- Previous attempts to promote therapeutic revascularization in the heart have failed.
- Understanding the heart's poor angiogenic capacity is crucial for treating heart disease.
Purpose of the Study:
- To investigate why the heart is a poorly angiogenic environment compared to skeletal muscle.
- To compare the angiogenic response of cardiac and skeletal muscle endothelial cells.
- To identify molecular mechanisms underlying differential angiogenesis.
Main Methods:
- Utilized a lineage tracing approach in mice to genetically label sprouting endothelial cells.
- Compared the angiogenic response to vascular endothelial growth factor (VEGF) in cardiac and skeletal muscle.
- Investigated the role of Apelin and Notch signaling in endothelial cell behavior.
- Implanted cancer cells in different organs to assess tumor angiogenesis.
Main Results:
- Skeletal muscle showed robust angiogenesis with VEGF, forming new capillaries and arterioles.
- Cardiac muscle exhibited a blunted response to VEGF, with limited new arteriole formation.
- Apelin expression was induced in both muscle types, but only skeletal muscle endothelial cells successfully sprouted and formed vessels.
- Cardiac endothelial cells expressing Apelin failed to proliferate and form mature vessels, impacting tumor growth.
Conclusions:
- Cardiac endothelial cells activate Apelin but fail to proliferate and form structured vessels, unlike skeletal muscle cells.
- The heart's limited angiogenic potential contributes to reduced tumor angiogenesis and growth.
- These findings highlight intrinsic differences in endothelial cell behavior between cardiac and skeletal muscle.
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.
