Notch signalling in healthy and diseased vasculature

Abstract

Notch signalling is an evolutionarily highly conserved signalling mechanism governing differentiation and regulating homeostasis in many tissues. In this review, we discuss recent advances in our understanding of the roles that Notch signalling plays in the vasculature. We describe how Notch signalling regulates different steps during the genesis and remodelling of blood vessels (vasculogenesis and angiogenesis), including critical roles in assigning arterial and venous identities to the emerging blood vessels and regulation of their branching. We then proceed to discuss how experimental perturbation of Notch signalling in the vasculature later in development affects vascular homeostasis. In this review, we also describe how dysregulated Notch signalling, as a consequence of direct mutations of genes in the Notch pathway or aberrant Notch signalling output, contributes to various types of vascular disease, including CADASIL, Snedden syndrome and pulmonary arterial hypertension. Finally, we point out some of the current knowledge gaps and identify remaining challenges in understanding the role of Notch in the vasculature, which need to be addressed to pave the way for Notch-based therapies to cure or ameliorate vascular disease.

Pericytes: The lung-forgotten cell type

“…PDGFRβ knockout embryos lack pericytes and vSMCs and thus PDGFRβ expression is not specific to pericytes ( Noskovičová et al, 2014 ). PDGFRs are activated by the binding of ligands which triggers consequent cell signalling cascades that regulate cell proliferation, differentiation, migration, mural cell coating, and survival ( Thijssen et al, 2018 ; Del Gaudio et al, 2022 ).…”

“…The PDGF-B/PDGFRβ signalling axis serves as a paracrine endothelium-to-mural cells signalling loop which is initiated in the endothelium where the PDGF ligand is produced and secreted and receptor activation drives the differentiation of mesenchymal progenitor cells to mural cells and promotes mural cell coating of the blood vessels ( Gaengel et al, 2009 ; Del Gaudio et al, 2022 ). PDGF-B/PDGFRβ signalling mediates the recruitment of pericytes to the endothelial cells of new vessels thus providing support and secreting additional cytokines to aid in angiogenesis ( Thijssen et al, 2018 ).…”

“…The mechanism behind Notch-mediated pericyte survival was determined to be regulation of PDGFRβ levels ( Nadeem et al, 2020 ). However, there is conflicting evidence surrounding how Notch3 function affects pericytes depending on the model investigated–Notch3 −/− mice ( Henshall et al, 2015 ), diabetic Notch3 −/− mice ( Liu et al, 2018 ), zebrafish ( Wang et al, 2014 ), or in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) ( Dziewulska and Lewandowska, 2012 ; Del Gaudio et al, 2022 ). Therefore, further investigations into how Notch signalling affects pericytes is needed.…”

A perspective on Notch signalling in progression and arrhythmogenesis in familial hypertrophic and dilated cardiomyopathies

“…These data support the need for further investigation of mechanisms related to Notch especially in the early stages of disease progression. These studies could include Notch associated mechanisms related to sprouting and splitting angiogenesis induced by ischaemia in the micro-environment [52,53]. One study exemplifying possible approaches investigated the angiogenic factor canopy 2 in a mouse pressure overload model and reported that expression of the factor produced beneficial effects in the progression from hypertrophy to dilated failure [54].…”

Roles of Notch Signaling in the Tumor Microenvironment

“…Notch signaling is key regulator of normal vascular development. The roles of Notch in normal vascular biology range from serving a critical role in the first phase of vascular development, i.e., vasculogenesis, during which loss of Notch signaling leads to an aberrant vascular bed and embryonic death in mouse models with perturbed Notch signaling; for review, see [ 138 ]. Notch signaling is furthermore important for establishing the arterial and venous sides of the endothelium, as well as for sprouting of the blood vessels during angiogenesis.…”