Notch Signaling in Endothelial Cells: Is It the Therapeutic Target for Vascular Neointimal Hyperplasia?

Abstract

Blood vessels respond to injury through a healing process that includes neointimal hyperplasia. The vascular endothelium is a monolayer of cells that separates the outer vascular wall from the inner circulating blood. The disruption and exposure of endothelial cells (ECs) to subintimal components initiate the neointimal formation. ECs not only act as a highly selective barrier to prevent early pathological changes of neointimal hyperplasia, but also synthesize and release molecules to maintain vascular homeostasis. After vascular injury, ECs exhibit varied responses, including proliferation, regeneration, apoptosis, phenotypic switching, interacting with other cells by direct contact or secreted molecules and the change of barrier function. This brief review presents the functional role of the evolutionarily-conserved Notch pathway in neointimal hyperplasia, notably by regulating endothelial cell functions (proliferation, regeneration, apoptosis, differentiation, cell-cell interaction). Understanding endothelial cell biology should help us define methods to prompt cell proliferation, prevent cell apoptosis and dysfunction, block neointimal hyperplasia and vessel narrowing.

Integrin β3 Mediates the Endothelial-to-Mesenchymal Transition via the Notch Pathway

“…Mammals express four Notch transmembrane receptors (Notch-1, Notch-2, Notch-3, and Notch-4) and five typical transmembrane ligands (Delta-like 1 [Dll-1], Dll-3, Dll-4, Jagged-1, and Jagged-2). As mentioned, different combinations of Notch receptors and their ligands can play different roles in EC behavior [1]. Noseda et al [16] provided the first evidence that Notch activation in ECs results in morphological, phenotypic, and functional changes and induces the EndMT.…”

“…The damage to ECs initiates the development of neointimal hyperplasia and endothelial regeneration occurs to restore the protective barrier at the end of the neointimal hyperplasia [18]. In addition, VSMC proliferation and migration are common characteristics of neointimal hyperplasia; ECs also contribute to neointimal hyperplasia as a source of smooth muscle-like cells [1]. We and others have previously shown that ECs can acquire a fibro-proliferative mesenchymal phenotype through the EndMT under pathological conditions [3,6].…”

“…Neointimal lesions mainly comprise smooth muscle-like cells. The endothelium is a source of smooth muscle-like cells and contributes to neointimal hyperplasia through the endothelial-to-mesenchymal transition (EndMT) [1,3]. However, little is known about the mechanism regulating this process.…”

“…Neointimal hyperplasia is responsible for stenosis, which requires corrective vascular surgery such as arteriovenous fistula surgery and stent angioplasty, and is also a major morphological feature of many cardiovascular diseases such as atherosclerosis and hypertension [1]. The initiating event in neointimal hyperplasia is endothelial cell (EC) damage.…”

Disease-relevant single cell photonic signatures identify S100β stem cells and their myogenic progeny in vascular lesions

“…Furthermore, Notch signalling may direct lesion formation by modulating the function of EC, SMCs, macrophages and stem cells [31][32][33][34][35][36] .…”