Review article
Coronary vessel formation in development and regeneration: origins and mechanisms

https://doi.org/10.1016/j.yjmcc.2022.03.009Get rights and content

Highlights

  • Endothelial cells from multiple developmental origins integrate to form a functional coronary vascular network.

  • Preexisting coronary endothelial cells is the dominant source of cells to mediate neovascularization after cardiac injury.

  • The development and growth of coronary vessels emanated from different cellular origins are governed by distinct regulatory mechanisms.

  • Reactivating or recapitulating mechanisms of coronary vessel formation could facilitate therapeutic revascularization in ischemic heart disease.

Abstract

Neovascularization of the ischemic myocardium following infarction is vital for the survival of cardiomyocytes and prevention of heart failure. However, the intrinsic revascularization following ischemic injury in the heart is inadequate to restore blood flow to the infarcted myocardium. A comprehensive understanding of how coronary vasculature is constructed and what developmental pathways might be reactivated after infarction is beneficial to develop effective strategies for heart revascularization. The latest lineage tracing studies of coronary vasculature have revealed multiple developmental origins for coronary vascular endothelial cells. The development and growth of coronary vessels emanated from different cellular origins are governed by distinct regulatory mechanisms. Here, we highlight recent research advancements on cellular sources and molecular mechanisms of coronary vessel formation during heart development and regeneration, and also elaborate on how these mechanisms can be reactivated or recapitulated to facilitate therapeutic revascularization in ischemic heart disease.

Introduction

The coronary arteries nourish the continuously pumping cardiac muscle with oxygen and nutrients by delivering fresh, oxygenated blood. A heart attack or acute myocardial infarction (MI) can occur when coronary artery is occluded, causing the death of billions of cardiomyocytes in the downstream infarction region[1]. The adult mammalian heart cannot functionally repair and regenerate itself after injury[2]. The damaged myocardium is replaced by scar tissue, which causes adverse effects on cardiac pump function and eventually leads to heart failure[1]. Depending on the severity of the disease, medical therapy, angioplasty and stenting, or coronary artery bypass grafting (CABG) can be optioned to treat coronary artery disease (CAD) [3,4]. Yet, CAD remains the leading cause of mortality worldwide and produces immense health and economic burdens globally[5]. Thus, the development of improved approaches to promote revascularization in ischemic adult heart is imperative[6,7].

Coronary arteries are composed of 3 major cell types: endothelial cells (ECs) (inner layer), smooth muscle cells (middle layer), and adventitial fibroblasts (outermost layer)[8]. During the development of coronary artery, the endothelial layer of the artery is first formed. Then smooth muscle cells and fibroblasts are recruited to assemble mature coronary arteries. In the adult heart, coronary ECs are heterogenous as they form arteries, veins, and capillaries. The endothelium is the location where most vascular diseases occurs in adults such as atherosclerosis and thrombosis[9,10]. Hence, uncovering the cellular and molecular mechanisms regulating coronary endothelial differentiation and specification in development is crucial for understanding many congenital anomalies of coronary arteries, recapitulating the developmental programs and devising novel effective therapeutic strategies for cardiovascular regeneration[6,7]. In this review, we mainly focus on coronary vascular ECs (VECs), and elaborate on their cellular origins and the molecular mechanisms regulating coronary vessel formation during heart development and after injuries.

Section snippets

Multiple origins of coronary ECs in developing heart

The developing heart at E10.5 is made of endocardium, myocardium, and epicardium[11]. In mouse early embryonic development (before E10.5), the avascular heart consists of thin myocardium lined by the endocardium and receives oxygen and nutrients through passive diffusion of blood in cardiac lumen. Subsequently, as the myocardium grows, passive diffusion from chamber is insufficient to nourish the thickening myocardial wall. Immediately after initiation of contraction, preliminary vascular

Cellular sources for coronary neovascularization during cardiac repair

Revascularization of the injured region is one of the effective therapeutic approaches for acute MI[62]. The proposed potential cellular sources for coronary neovascularization in cardiovascular repair include bone marrow-derived endothelial progenitor cells (EPCs), cardiac fibroblasts, endocardial cells, and preexisting coronary ECs (Fig. 2).

Collateral artery formation

Collateral arteries are a unique artery subtype that bridge two conventional arteries, forming a natural bypass to restore blood reperfusion downstream of vascular occlusion[121,122]. Collateral coronary arteries as a natural bypass could be induced to increase survival of patients with CAD[123]. To date, 3 models of collateral artery formation have been proposed, namely arterialization[124], arteriogenesis[125], and artery reassembly[123] (Fig. 3). During arterialization, enlarged capillaries

Coronary endothelial progenitors from different origins respond to distinct molecular pathways

It is now generally accepted that complementary SV- and endocardial-derived endothelium converge to produce the vast majority of the coronary vasculature. Extensive research provides evidence that coronary endothelial progenitors emanating from different origins respond to distinct regulatory pathways. Fog2 (friend of GATA-2)- mutant mice with impaired subepicardial coronary sprouting from the SV and instead exhibit an overproduction and enlargement of ectopic blood islands derived from

Conclusions and perspectives

The endogenous neovascular response to ischemic injury in the heart is insufficient to restore blood flow to infarcted myocardium. Unraveling cellular sources and molecular mechanisms of coronary vessel formation during heart development and regeneration provides important insights into developing effective strategies for heart revascularization. With the technological advances in genetic lineage tracing and imaging as well as single cell RNA technology, significant progress has been made in

Declaration of Competing Interest

None declared.

Acknowledgements

This work was supported by National Key Research & Development Program of China (2021YFA1101900, 2018YFA0107900, 2019YFA011040, and 2019YFA080200), National Science Foundation of China (81872132, 82088101, 32050087, and 31730112), Ten Thousand Talent Program for Young Top-notch Talent.

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