Notch signalling in ischaemia-induced angiogenesis

Abstract

Notch signalling represents a key pathway essential for normal vascular development. Recently, great attention has been focused on the implication of Notch pathway components in postnatal angiogenesis and regenerative medicine. This paper critically reviews the most recent findings supporting the role of Notch in ischaemia-induced neovascularization. Notch signalling reportedly regulates several steps of the reparative process occurring in ischaemic tissues, including sprouting angiogenesis, vessel maturation, interaction of vascular cells with recruited leucocytes and skeletal myocyte regeneration. Further characterization of Notch interaction with other signalling pathways might help identify novel targets for therapeutic angiogenesis.

Figure 1. Notch signalling and cellular components involved in the post-ischaemic regenerative process

Decreased oxygen levels (hypoxia) resulting from arterial occlusion activates Notch signalling in satellite cells (1), which results in expansion of satellite cells and reduced expression of myogenic differentiation genes, MyoD and desmin. Furthermore, hypoxia triggers the expression HIF-1α (2), which subsequently binds to NICD and enhances the transcription of Notch target genes. In hypoxic areas, VEGF-A production is activated by HIF-1α through binding to the VEGF promoter. Endothelial cells exposed to the VEGF-A gradient express Dll4 and are selected as tip cells that sprout and send filopodia (3). Endothelial tip cells use Dll4 to activate Notch on neighbouring stalk cells and thereby suppress the expression of the VEGF receptors Kdr, Flt4 and Nrp1. This prevents stalk cells from acquiring a tip cell phenotype. Infiltrating leucocytes may amplify the angiogenic response by secreting VEGF-C and TNFα (4). TNFα induces the expression of Jag1 on tip cells. VEGF-C binds Flt4, which is highly expressed in tip cells. Activation of Notch in stalk cells allows for recruitment of mural cells (pericytes), through a mechanism involving EphrinB2, and stabilization of neovascularization (5). Vascular maturation is also supported with the contribution of Notch3 and Dll1 in the recruitment of VSMCs of collateral arterioles (6). Kdr, VEGFR-2; Flt4, VEGFR-3.