Coronary vessel formation in development and disease: mechanisms and insights for therapy

Abstract

The formation of new blood vessels after myocardial infarction (MI) is essential for the survival of existing and regenerated cardiac tissue. However, the extent of endogenous revascularization after MI is insufficient, and MI can often result in ventricular remodelling, progression to heart failure and premature death. The neutral results of numerous clinical trials that have evaluated the efficacy of angiogenic therapy to revascularize the infarcted heart reflect our poor understanding of the processes required to form a functional coronary vasculature. In this Review, we describe the latest advances in our understanding of the processes involved in coronary vessel formation, with mechanistic insights taken from developmental studies. Coronary vessels originate from multiple cellular sources during development and form through a number of distinct and carefully orchestrated processes. The ectopic reactivation of developmental programmes has been proposed as a new paradigm for regenerative medicine, therefore, a complete understanding of these processes is crucial. Furthermore, knowledge of how these processes differ between the embryonic and adult heart, and how they might be more closely recapitulated after injury are critical for our understanding of regenerative biology, and might facilitate the identification of tractable molecular targets to therapeutically promote neovascularization and regeneration of the infarcted heart.

Key points

  • The coronary vasculature is established in mammals during embryonic and neonatal development, with endothelial cells derived predominantly from the sinus venosus and the endocardium, and mural cells mainly from the epicardium.

  • Neovascularization after myocardial infarction is essential for the restoration of blood flow to the injured myocardium, but the endogenous mechanisms by which new vessels grow is poorly understood.

  • To date, no effective treatment to induce coronary neovascularization has been identified.

  • The neonatal mouse heart has greater regenerative capacity than the adult mouse heart.

  • The regulatory pathways that control angiogenesis during development are activated in the injured myocardium in the neonatal mouse heart, but are repressed or not activated in the infarct region in the adult mouse heart.

  • Genetic cell lineage tracing and single-cell transcriptomic analyses might provide insights into mechanisms that can be targeted to increase the neovascularization and regeneration of the injured myocardium.

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Fig. 1: Development of the embryonic coronary vasculature.
Fig. 2: Molecular mechanisms that control formation of the coronary vasculature.
Fig. 3: Proposed mechanisms of coronary neovascularization after myocardial infarction.
Fig. 4: Regulatory pathways in coronary vessel development.

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Acknowledgements

The authors are supported by funding from the British Heart Foundation: a DPhil studentship to I.-E. L. (FS/12/69/30008), a senior fellowship to S.D.V. (FS/17/35/32929), an Ian Fleming fellowship to N.S. (FS/19/32/34376), and project grants to S.D.V. and N.S. (PG/16/34/32135 and PG/18/62/33967). The authors are also supported by the Oxbridge BHF Centre of Regenerative Medicine (RM/17/2/33380) and the BHF Oxford Centre of Research Excellence (RE/13/1/30181).

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I.-E.L. and N.S. wrote the article and contributed to the discussion of its content. All authors researched data for the article and reviewed and edited the manuscript before submission.

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Correspondence to Nicola Smart.

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Glossary

Angiogenesis

The process by which new blood vessels arise from pre-existing vessels, typically by sprouting or splitting.

Arteriogenesis

The remodelling of pre-existing, interconnecting vessels into larger arteries. During development, this process is accompanied by mural cell recruitment.

Neovascularization

The formation of new blood vessel networks capable of perfusion, for example, to replace those damaged by myocardial infarction.

Vascular plexus

A primitive network of vessels that forms initially during development before undergoing differentiation and remodelling to give rise to vessels of different sizes and types.

Proepicardial organ

A transient developmental outgrowth of mesothelial cells arising in the region of the septum transversum (embryonic days 8.5–9.5 in mice). Cells of the proepicardium delaminate over the outer surface of the heart to give rise to the epicardium.

Septum transversum

A sheet of mesoderm-derived tissue that forms in the mammalian embryo to separate the thoracic and abdominal cavities. Later in development, the septum transversum gives rise to the diaphragm and ventral mesentery.

Epicardium

A mesothelial layer of cells on the outer surface of the heart, which contributes progenitor cells to the embryonic heart and stimulates sprouting of vessels from the sinus venosus.

Sinus venosus

The venous inflow tract of the embryonic heart that is continuous with the atria. The sinus venosus contributes a large proportion of coronary endothelial cells during embryonic stages. Later in development, the sinus venosus is incorporated into right atrium and coronary sinus veins.

Cre–loxP-based cell lineage tracing

A bacteriophage recombination system that is used predominantly in mouse and fish studies to genetically label a cell and trace its progeny.

Endocardium

The innermost layer of tissue that lines the chambers of the heart, comprising a specialized type of endothelial cell.

Single-cell RNA sequencing

The sequencing of an entire transcriptome at the level of individual cells to reveal heterogeneity between different cells, for example, those that make up a particular tissue or organism.

Blood island

A cluster of primitive erythroblasts surrounded by an endothelial covering that gives rise to early blood-filled vessels.

Mural cells

Support cells that surround the endothelium of blood vessels, with important roles in vessel development, homeostasis and stability. Mural cells include pericytes of the microcirculation and vascular smooth muscle cells that densely surround large arteries in multiple layers.

Collateral artery

New arterial segments that bridge two original arteries, forming a natural bypass to ensure blood flow downstream of an obstruction.

Pericytes

Mural support cells that wrap around the endothelium of capillaries and venules, and have important homeostatic roles in vessel maintenance and regulation of blood flow.

Epithelial-to-mesenchymal transition

A process by which epithelial cells, such as those of the epicardium, lose polarity and cell–cell contacts and transition into mesenchymal cells, characterized by a more migratory phenotype, which subsequently differentiate into fibroblasts or mural cells (in the case of epicardium-derived cells).

Neural crest

A transient embryonic cell lineage that gives rise to the peripheral nervous system, as well as non-neural cell types, including vascular smooth muscle cells, pigment cells and cells of craniofacial bones, cartilage and connective tissue.

Endothelial progenitor cells

Circulating cells that express some markers that define vascular endothelial cells, as well as markers associated with some stem cells, and are thus considered a type of progenitor cell. Upon appropriate stimulation, endothelial progenitor cells have been shown to differentiate into endothelial-like cells in vitro.

Arterialization

The sprouting of capillaries into the ischaemic region and transformation into arteries by recruitment of vascular smooth muscle cells.

Clonal expansion

Formation of a group of identical cells that arises from a single cell by proliferation.

Endothelial-to-mesenchymal transition

The transformation of endothelial cells into mesenchymal cells, which can subsequently differentiate into fibroblasts or mural cells.

Watershed

A region of the heart that receives blood from distal branches of two large coronary arteries, such as the capillary network at the anterior midline of the heart.

Mitogenic stimulation

Treatment with one or more growth factors, typically peptides, to induce a cell to undergo division and proliferate.

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Lupu, IE., De Val, S. & Smart, N. Coronary vessel formation in development and disease: mechanisms and insights for therapy. Nat Rev Cardiol 17, 790–806 (2020). https://doi.org/10.1038/s41569-020-0400-1

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