From pumps to pipes: A special issue on mechanisms of cardiovascular development

In this special issue on “Mechanisms of cardiovascular development,” we present a series of studies that explore key questions in cardiovascular developmental biology and regeneration. In recent decades, the broad field of cardiovascular development has expanded to encompass new areas of investigation such as organ specific vascular networks, regeneration of the heart and vessels, as well as the role of the non-coding genome.

We kick off with two comprehensive review articles, one by Beisaw and Wu¹ explores cardiomyocyte maturation and its regulation in cardiac regeneration. In particular, the mechanisms that control myofibril maturation, the metabolic processes underlying maturation and polyploidization of cardiomyocytes are extensively reviewed, and how these processes are altered in regeneration outlined in detail. Payne et al.,² then provide a detailed overview of the transcription factors that control developmental angiogenesis and vasculogenesis. This helpful resource, points readers to detailed information on binding motifs, phenotypes in mice and zebrafish, and gaps in the current understanding of transcriptional control of vascular development. These reviews set the scene for a series of seven research articles.

In cardiac development, Auman et al.,³ genetically map a zebrafish mutant with pleiotropic phenotypes including loss of pectoral fins and a string-like heart. They discover that smarcc1a controls heart chamber development following normal specification of the early cardiac field. In particular, smarcc1a controls the normal formation of the atrioventricular canal (AVC, which contains the future valves), identifying an unappreciated regulator of this process. Furthermore, uncovering new understanding of how the valve territories are regulated, but this time using mouse models, Okumura et al.,⁴ explore the role of Hey2. Hey2 knockout (KO) mice at P0 were found to have ventricular septal defects (VSDs) and tricuspid valve malformations. Conditional KO mice reveal that function of Hey2 is essential in developing myocardium for normal development of the septum and valves. The complex phenotypic description here is aided by reconstructed 3D images generated from H&E sections using freely available software, a resource that may be of value to many more groups in the future.

The trabeculae of the heart form finger-like projections in development that arise from the compact myocardium and serve to thicken the maturing heart wall. This occurs while the developing heart is contracting. In this issue, Olejnickova et al.⁵ use simulation of electrical conduction in 3D models of wildtype and trabecular-deficient chick embryos. They combine modeling with detailed analysis of genetic and pharmacological trabecular deficient models to find that trabeculae support normal conduction and development.

Maturation of the heart also involves the formation of an organ-specific vascular network to support tissue growth and function. ZFP57 is a regulator of chromatin methylation that can have distinct maternal and zygotic functions. In a study that uses elegant mutant combinations, it is shown that loss of both maternal and zygotic Zfp57 leads to a surprisingly selective loss of coronary vasculature (Zhao and Zhao).⁶ While it is clear that these mice also have defects in myocardial maturation, and the precise cellular interactions underpinning phenotypes remain to be fully understood, this study discovers a surprising regulator of coronary vessel development. Shifting to development of other vascular lineages, this issue reveals an unappreciated source of vasculature in the developing thyroid. Amniogenic somatopleure cells (ASCs) derived from the somatopleure and contribute to the extraembryonic membrane that surrounds the embryo: the amnion. However, they can also contribute to the embryo. Haneda et al.,⁷ use quail chick chimera analysis to show that intraembryonic ASCs in pharyngeal regions contribute to the developing vasculature of the thyroid. They use single-cell sequencing and explants of ASCs to suggest the presence of hemangioblast-like cells that respond to FGF and VEGF in the early but not late amnion. This work represents a new contribution to our growing understanding of diverse origins for vascular endothelial cells.

Vessels are surrounded by important mural cell lineages, including the vascular smooth muscle cells (vSMCs). In the pharyngeal region of the embryo, cardiac neural crest-derived cells migrate into aortic arches to form vSMCs. Here, Alexander et al.,⁸ comprehensively examine conditional knockouts of SMAD4 in different pharyngeal cell types and conclude that SMAD4 is essential for normal NCC contributions to vSMCs. However, in an intriguing turn, they also suggest a compensatory cellular contribution in the absence of SMAD4. This large body of work reveals new insights into how vSMCs develop at pharyngeal arteries.

Finally, a special edition on cardiovascular mechanisms would not be complete without new insights into how the heart regenerates and in this case, how cells including the endocardium interact to regulate regeneration. A study in zebrafish by Shin et al.,⁹ investigates an enhancer element associated with regeneration at the leptinb locus. Re-analyzed single-cell studies implicate leptinb expressing endocardial cells as producing regenerative factors. They find that the leptinb enhancer is activated in the endocardium and epicardium upon injury and essential for normal leptinb expression, but not expression of other surrounding genes. This work develops useful new tools and single-cell resources to help dissect how different cell types interact to orchestrate cardiac regeneration in the zebrafish.

The group of articles and reviews submitted to this special issue serve to nicely illustrate several current questions and research directions in cardiovascular development and regeneration. This is a field with many open questions, many new and exciting tools and enormous opportunity for discovery.