doi: 10.1161/CIRCRESAHA.108.173039
© 2008 American Heart Association, Inc.
Editorials |
Myocardial–Coronary Interactions
Against the Canon
From the Department of Animal Biology, Cardiovascular Development and Angiogenesis Group, Faculty of Science, University of Málaga, Spain.
Correspondence to José M. Pérez-Pomares, PhD, Department of Animal Biology, Faculty of Science, University of Málaga. Campus de Teatinos s/n, 29071 Málaga, Spain. E-mail jmperezp{at}uma.es
See related article, pages 615–623
Key Words: embryo • heart • PCP • vangl2 • coronary development
Interaction between cardiac embryonic tissues is essential to the normal progression of heart morphogenesis. Initially, the tubular outline of the vertebrate heart is constituted of only myocardium and endocardium. Both tissues are derivatives of the specified mesodermal precardiac progenitors that conform the so-called "heart fields."1 Later on (from HH18 [Hamburger and Hamilton stages of chick development] in the chick embryo and embryonic day 9.5 in the mouse), a third, primarily non–heart field–related cardiac cell lineage, the epicardium, spreads over the myocardium to form the outermost cell layer of the heart.2 From very early on, intercrossed signals from these 3 tissues act in an instructive manner, actively promoting and guiding the development of multiple cardiac structures. Among them, heart valves,3 ventricular trabeculae,4 compact myocardium,5 and epicardium/coronary vessels6 must be regarded as the most relevant ones.
Coronary vessels are absolutely required to sustain cardiac homeostasis, as evidenced by the dramatic effects of coronary ischemia or coronary congenital malformations,7 and for that reason, the morphogenesis of coronary vessels is of enormous importance. The formation of coronary blood vessels remains an exciting research subject in the field of cardiovascular development. Coronary development is a complex, progressive event, and it is well known that the formation of the epicardium is closely linked to that of coronary vessels. This is so because the subepicardium (ie, the extracellular matrix sandwiched between the epicardial epithelium and the myocardium) is the physical environment in which coronary vasculogenesis is initiated but also because the epicardium and its progenitor tissue, the proepicardium, contribute to the endothelial, smooth muscle, and fibroblastic populations of the developing coronary vessels.2
The origin(s) of the different coronary cell types is quite relevant. Experimental approaches to trace the source of coronary cell progenitors in avians (in vivo retroviral tagging and quail-to-chick proepicardial chimeric transplantations8,9 and in vitro cell culture10) and mammals (protein expression and transgenesis11,12) strongly suggest that coronary vessels are, in terms of their origin, an authentic mosaic. In this regard, the examples provided by the recent use of some "epicardial-restricted" promoters12,13 to evaluate the contribution of a specific tissue to coronary development are also incomplete, mainly because the original constructs had been previously shown to have a partial, nonrestricted expression in the epicardial lineage.14 Finally, the quantitative contribution of the different possible sources of coronary progenitors (seemingly variable depending on the animal experimental model considered) and the mechanisms regulating arterio-venous differentiation and connections are still in need of extensive investigation.
In the conceptual frame of coronary morphogenesis, the myocardium has always been considered as a main player because of its signaling activities. Embryonic cardiac muscle has been reported to secrete to the subepicardium a variety of growth factors, such as vascular endothelial growth factor and basic fibroblast growth factor, known to be indispensable for vascular development to proceed.15 In turn, epicardially secreted, retinoic acid–dependent signals are required for the myocardium to proliferate and mature.5 However, this paracrine guidance of coronary formation by the myocardium is not likely to be the only morphogenetic link between the cardiac muscle and coronary vessels. Coronary vessels primarily develop in the subepicardial space, but their development soon proceeds by approaching to the myocardial surface until they end up lying over the outermost compact myocardium. In mice, the main coronary branches are finally embedded in this compact layer (see the Figure), whereas in avians and humans major coronary vessels remain subepicardial and only small caliber coronary vessels penetrate into the depth of cardiac muscle.15
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The study by Phillips et al in this issue of Circulation Research16 challenges this "secretory canon" on myocardial–coronary interactions by introducing a careful pool of evidence that beautifully shows how there is much more in between cardiac vessels and muscle than a simple paracrine interdependence. This piece of work is based in the phenotypic analysis of the loop-tail (Lp) mouse, in which the planar cell polarity (PCP) gene Vangl2 is disrupted. The study demonstrates that Vangl2 is exclusively expressed in the myocardium, and therefore, the finding of a severely impaired coronary development in the Lp mouse is surprising. This non–cell autonomous role of the myocardially active PCP in coronary vessel morphogenesis emphasizes the importance of alternative, nonparacrine tissue interactions during heart development.
The PCP signaling pathway plays a crucial role in metazoan development by determining critical aspects of histogenesis, namely tissue polarity. In the context of epithelial or epithelial-like tissues, "polarity" does not refer to cell organization around a basoapical axis but to a characteristic cell orientation in the plane of the epithelium. PCP signaling was originally described in Drosophila as involved in the planar polarization of the epithelial cuticle in the adult fly, being the 2 best known examples for this phenomenon, the proximodistal polarization of the wing epithelium (evidenced by the orientation of the single hairs present in every cell) or the characteristic arrangement of ommatidia in the eye.17,18 Molecules involved in the PCP pathway commonly fall into 1 of these 3 categories: (1) the "upstream" factors in charge of the coordination of the planar polarity across the whole tissue (eg, some atypical cadherins like Dachsous and Fat); (2) the so-called "core polarity genes" that provide intrinsic polarization cues within single cells through their uneven subcellular localization; and (3) the tissue-specific factors needed for the emergence of the polarized structures characteristic of each cell type.18 One of the first elements of the pathway described was the Drosophila frizzled (fz), which belongs to the second, core polarity type. It is well known that fz, a 7-pass transmembrane protein in the fly, can act as a receptor for the wingless (wg) ligand, initiating a signaling cascade that in vertebrates, includes the secreted Wnts, the frizzled receptors, and the β-catenin/TCF–LEF complex. This is referred to as the "canonical" Wnt signaling pathway. Alternatively, as already indicated, frizzled has pivotal functions in the PCP, a different signaling pathway that does not involve important elements of the canonical cascade. A specific controversy exists on the relevance of the diffusible wg/Wnts because molecules are thought to be dispensable for PCP signaling initiation in Drosophila but seem to be required for the activation of the pathway in vertebrates. However, it has been proposed that the set of Wnts activating the vertebrate PCP would be clearly different from those responsible for the triggering of the canonical pathway.19
Vangl2, like Dishevelled, Flamingo, Prickled, or Diego, is a PCP core polarity gene. Together with other molecules in the pathway, it modulates actin cytoskeleton through the small GTPases RhoA and Rac and the downstream Rho kinase (ROCK). Vangl2 is thus partially responsible for a variety of changes in cell adhesion, polarity, and short-range tissue movements.18 In summary, activation of PCP signaling in a given cell population is able to exert changes in neighboring cells that do not express PCP elements.
The study by Philips et al shows how alterations in myocardial PCP signaling can severely impair the coronary network that develops in close apposition to the myocardium. Defects in coronary vessels include enlarged, disorganized, and unstable blood vessels with the frequent appearance of wide blood-island–like structures, suggesting that the mechanics of coronary vasculogenesis (angioblast coalescence and vascular assembly) is hampered in the Lp mouse. However, no gross changes in the spatial patterning of coronaries could be recorded in the Lp mouse, and the malformed or immature vessels are, in general, located in the heart regions where they are expected to mature into the main adult coronary vessels. This finding is extremely interesting because it suggests it is the short distance myocardium–coronary interaction what is altered in the Vangl2 mutant. Phillips et al discuss the issue in terms of the possible changes taking place in the migration of coronary precursors over and into the compact myocardial layers. The first scenario, ie, horizontal migration of coronary cells over the myocardial surface, deserves attention because abnormal migration of coronary cell progenitors over the cardiac muscle would prevent the generation of a spatial prepatterning for coronary vessels, unless the differentiation of coronary cell precursors had previously taken place in situ from the epicardium. The second scenario (ie, vertical immigration of coronary precursor cells into the depth of the myocardium) is, in its own way, supporting the concept of intramyocardial vasculogenesis as a possible specific mechanism accounting for myocardial vascularization,10,15 therefore pointing to a continuous extension of vasculogenesis from the subepicardium toward the myocardium.
Previous studies from Dr Henderson’s laboratory have shown the importance of PCP in heart morphogenesis.20,21 Disruption of myocardial polarized movements can affect proximal outflow tract muscularization and produce abnormal arterioventricular connection (double outlet right ventricle) and even cardiomyopathy. The characteristics of normal versus abnormal polarization in the myocardium could be recorded in one of these studies by monitoring the orientation of the myocardial lamellipodia and filopodia as they extended into the conal endocardial cushions.20 To define the nature of the polarization of compact layer myocardiocytes is obviously a more complex issue, and thus the study by Phillips et al simply states a "myocardial disorganization" in the Lp mouse heart. The authors, who had previously suggested that ROCK could be downstream Vangl2,20 make an important point by showing that myocardial-specific ROCK function disruption mirrors the coronary phenotype found in the Lp mouse, including disorganization of the actin cytoskeleton. ROCK1 and -2 are expressed in both the myocardium and the epicardium, and for that reason the strategy chosen by Phillips et al to dissect the implication of ROCK in the phenotype (MLC2V-CrexROCK-CAT dominant negative mice cross) is appropriate because it avoids the possibility of epicardial-dependent coronary defects. Hopefully, further studies will improve our understanding of this important aspect of myocardial histogenesis.
Finally, it is possible to envision another change in the weak "canon" on the involvement of Wnts in cardiac development.19 This new view would be based on the dual role played by molecules like Wnts, frizzled or Dishevelled, all of which could act in a compatible, parallel fashion to signal through β-catenin–dependent canonical or β-catenin–independent "noncanonical" pathways, ultimately converging at the anatomic level in the form of mature and functional coronary vessels.
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Acknowledgments |
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The author thanks Dr R. Muñoz-Chapuli for critical reading of the manuscript and helpful discussions, as well as Dr M.E. Manjón-Cabeza for expert help in the design of the illustration of this editorial. I apologize to all the researchers whose work could not be cited because of space constraints.
Sources of Funding
This work was supported by grants from the Spanish Ministry of Science and Education (BFU2005-00483), an Excellence in Research grant from the Andalucian Government (P06-CTS-01614), and European Union Sixth Framework Programme contract ("HeartRepair") LSHM-CT-2005-018630. This editorial reflects only the views of the author, and the European Union Sixth Framework Programme contract ("HeartRepair") is not liable for any use that may be made of the information contained herein.
Disclosures
None.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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Related Article:
Circ. Res. 2008 102: 615-623.
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