Cardiovascular diseases are the leading cause of death in Europe1. It is well established that ageing, obesity, hypertension or physical inactivity are major risks for developing cardiovascular disease. Heart failure is associated with remodelling and functional impairment of the microvasculature2, and the protection of the vasculature from the adverse effects of cardiovascular disease might prevent, though not reverse, progression of the disease3.
Exercise protects against the development of cardiovascular diseases, but how this happens at the cellular level is not very well understood. In a study recently published in eLife, Hemanthakumar et al.4 have shown that cardiovascular disease risk factors like obesity and hypertension induce many cardiac disease features like mesenchymal gene expression, inflammation, vascular permeability, oxidative stress, and collagen synthesis. Interestingly, the authors found that exercise training was able to attenuate most of the molecular pathways induced by these cardiovascular disease risk factors.
Hemanthakumar and collaborators found that exercise training and different disease risk factors like age, obesity and hypertension have different and opposite effects on microvasculature structure and in the transcriptome of cardiac endothelial cells. To explore the response of cardiac endothelial cells, the authors isolated them and performed bulk RNA sequencing. Gene ontology analysis of the differentially expressed genes between the different groups showed that cardiovascular disease risk factors induce senescence and TGF-b signalling activation.
In particular, the authors identified a cluster of genes on which exercise training and the risk factors have opposite effects. They describe increased Serpinh1 expression induced by ageing and obesity, but reduced in exercised animals. Serpinh1 is a collagen chaperone that had been already linked to fibrosis5. Interestingly, the overexpression of SERPINH1 in human endothelial cells induces mesenchymal features, while its silencing inhibits collagen production and mesenchymal transition.
This study opens new doors to the study of the cellular and molecular effects of the different risk factors of cardiovascular disease. It provides a plethora of data to further study these effects, not only of the detrimental risk factors, but also the positive effects of exercise training. And finally, it raises important new questions. Endothelial cells in the heart have different developmental origins, and although they converge to equivalent states during development6. Therefore, it would be extremely interesting to explore whether all endothelial cells respond to the different inputs or if this mesenchymal response is taking place in a specific subpopulation. Endothelial cells are very plastic and dynamic, and mesenchymal activation of endothelial cells after a myocardial infarction has been shown to be transient7 as endothelial cells are able to recover their quiescent phenotype. Also, further experiments to determine whether healthier behaviors would be sufficient to revert the deleterious transcriptional shift of endothelial cells caused by age or obesity would be of interest. This study contributes to the better understanding of the damaging effects of cardiovascular risk factors by the scientific community and suggests potential future therapeutic approaches.