Ever since Leonardo da Vinci sketched the heart vessels in his anatomical notebook in the late fifteenth century, the origin of the coronary vasculature has been in question. We might just have come upon the answer.
As the heart grows, there comes a point at which it requires its own arteries and veins to survive. These coronary vessels ensure that blood-borne oxygen and nutrients reach the muscle of the heart-chamber walls as it thickens and expands to accommodate the circulatory needs of the developing embryo. A long-standing question has been where these resident heart vessels' endothelial cells (specialized cells that line the inner wall of vessels) and vascular smooth muscle cells (which make up the vessels' middle layer and offer mechanical support) come from. Red-Horse et al.1 report, on page 549 of this issue, that differentiated cells of an unexpected origin are the source of coronary vessels.
Benjamin Franklin once said, “Originality is the art of concealing your sources”, and, in this respect, the heart has been truly original. For more than a century, coronary vessels were thought, on the basis of anatomical observations, to simply bud off the aorta — the major vessel that circulates blood around the body — within the heart. However, these early data were challenged some 20 years ago by studies that revealed growth of coronary arteries into the aorta2. In addition, more recent experiments in chickens and quails3 presented the textbook view that the coronary vessels develop from the proepicardial organ (PEO), a transient structure in the embryo that contacts and spreads over the developing heart to form an outer (epithelial) layer called the epicardium. Nonetheless, subsequent lineage-tracing experiments in mice4,5 cast doubt on the PEO dogma, leaving the source of coronary endothelial cells open to debate.
Red-Horse et al.1 directly address the question of origin by performing a series of meticulous analyses. Through these, they demonstrate that the coronary vessels are primarily derived from differentiated endothelial cells that sprout off from a major vein located just above the developing liver, the sinus venosus, which returns blood to the embryonic heart. Although classical studies in dogfish6 have implicated the sinus venosus as the site of the earliest appearance of vessels in the heart, this vein was not previously recognized as the source of coronary-artery endothelial cells. Moreover, that these arterial cells should arise from a venous source implicates developmental reprogramming as the mechanism underlying coronary-artery formation.
The real strength of Red-Horse and colleagues' study lies in the careful and thorough approach taken throughout, as the devil really is in the detail. The authors focused on a mouse strain that expresses the reporter gene lacZ only in coronary endothelial cells and not in endocardial cells (commonly used endothelial markers often detect both cell types), thus ruling out a major contribution from the endocardium — the innermost tissue lining heart chambers — in coronary-vessel formation.
Indeed, with a series of striking images, the researchers convincingly show that endothelial cells emerge from the sinus venosus — a finding that is supported by their data1 showing expression of markers for new vessel formation in this region. What nicely complements their experimental data is parallel schematic illustrations to demarcate the progressive sprouting and development of both coronary arteries and veins (Fig. 1). This effort goes some way to compensate for the inherent disadvantage of using the mouse in such studies: namely, the inability to perform live imaging and time-lapse microscopy, which would have been invaluable to document the process in situ.
A two-pronged clonal analysis by Red-Horse et al. leaves no doubt about a sinus venosus contribution. In the first, they ingeniously mixed transgenic lacZ-expressing sinus venosus with wild-type epicardial tissue — and vice versa — and allowed them to grow together in culture. They found not only that vessels expressing lacZ emerged exclusively from transgenic sinus venosus grafts, but also that both vessel sprouting and outgrowth depended on signals from the wild-type ventricle–epicardial tissue. The identity of these signals remains unknown.
In the equivalent in vivo analysis, the authors tracked clones of coronary arteries, veins and capillaries back to cells expressing the VE-cadherin protein. This result is the strongest argument yet against a PEO origin for coronary arteries, because the cells of this structure do not express VE-cadherin. Even more intriguingly, perhaps, this represents visual evidence of endothelial-cell reprogramming, which is further supported by Red-Horse and colleagues' description of a cell-autonomous switch from signatures of venous to arterial gene expression.
The significance of these observations1 extends beyond the field of basic embryology. An understanding of both the origin of coronary vessels and the cell types that contribute to them during development is arguably an essential prerequisite for successfully stimulating the process of new vessel formation to treat coronary-artery disease in adult patients. Nonetheless, interesting questions remain for both developmental biologists and cardiologists.
For one, could it be that the PEO gives rise to a subpopulation (however minor) of endothelial cells and/or itself contributes progenitors to the sinus venosus? Indeed, both the PEO and sinus venosus might themselves arise from a common early progenitor-cell pool. Although Red-Horse et al. attempted to tackle these questions, further embryological studies, which will benefit from the development of improved lineage-specific genetic markers, are required to obtain unequivocal answers.
From a more translational research standpoint, identifying the molecular cues that promote developmental reprogramming of vasculature as described here — vein-to-artery 'switch' — and targeting such signals towards an equivalent venous cell population in the adult organ could facilitate the formation of new coronary vessels for re-vascularization of a diseased heart. Thus, Red-Horse and colleagues' work may represent the first tentative step towards engineering a non-surgical, coronary-artery bypass as a vascular therapy to counter the main cause of death worldwide.
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Circulation Research (2018)
Journal of Clinical Investigation (2017)
Biochemical and Biophysical Research Communications (2016)
Circulation Research (2016)
Nature Genetics (2016)