Role of Notch Signaling in Coronary Vessel Angiogenesis and Remodelling

Abstract

Coronary vessels supply the myocardium with nutrients and oxygen and are crucial for heart development and function. Coronary development defects result in coronary disease, a major cause of morbidity and mortality worldwide. The Notch signaling pathway is a highly conserved pathway, crucial for the regulation of cell specification and proliferation in specific tissue and organs. Specifically, the Notch pathway regulates the processes leading to the formation of the ventricular chambers; trabeculation, coronary vessel formation and trabecular compaction.ng. Later induced loss of Jag1 or Dll4 or gain of Dll4 or MFng leads to defective arterial specification, vascular malformations and aberrant coronary arterial patterning. Loss of Ephrinb2 phenocopies loss Jag1, and Ephrinb2 can rescue defective angiogenesis of Jag1- and Dll4-inactivated ventricular explants, identifying Ephrinb2 as a target of both ligands during coronary artery formation. Thus, Jag1 and Dll4/MFng have early opposing roles and late cooperative roles in coronary formation and the downstream direct target Ephrinb2 in endothelium and endocardium is a key effector molecule for the coronary arterial morphogenesis. Comparative transcriptome profiling of the different loss and gain of function mutant hearts revealed hypoxic, oxidative stress and cell death pathways and the activation of immune-inflammatory responses suggestive of ischaemic cell death. Thus perturbation of endocardial/endothelial Notch signaling severely disrupts coronary development and consequently myocardium proliferation and compaction, resulting in embryonic lethality. This implies that development of the coronary vessels and growth and maturation of the ventricles are two interlinked Notch-dependent processes.