Notch Signaling in Vascular Smooth Muscle Cells

Abstract

The Notch signaling pathway is a highly conserved pathway involved in cell fate determination in embryonic development and also functions in the regulation of physiological processes in several systems. It plays an especially important role in vascular development and physiology by influencing angiogenesis, vessel patterning, arterial/venous specification, and vascular smooth muscle biology. Aberrant or dysregulated Notch signaling is the cause of or a contributing factor to many vascular disorders, including inherited vascular diseases, such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, associated with degeneration of the smooth muscle layer in cerebral arteries. Like most signaling pathways, the Notch signaling axis is influenced by complex interactions with mediators of other signaling pathways. This complexity is also compounded by different members of the Notch family having both overlapping and unique functions. Thus, it is vital to fully understand the roles and interactions of each Notch family member in order to effectively and specifically target their exact contributions to vascular disease. In this chapter, we will review the Notch signaling pathway in vascular smooth muscle cells as it relates to vascular development and human disease.

Keywords: Notch signaling; Smooth muscle; Smooth muscle differentiation; Smooth muscle phenotype; Vascular development; Vascular disease.

Fig. 1

Notch family of ligands and receptors. Abbreviations: ANK, ankyrin repeats; Cys-rich, cysteine-rich region; DOS, Delta and OSM11-like proteins motif; DSL, Delta/Serrate/Lag2 motif; LNR, Lin12-Notch repeats; NECD, Notch extracellular domain; NICD, Notch intracellular domain; NLS, nuclear localization signal; NRR, negative regulatory region; PEST, proline/glutamic acid/serine/threonine-rich motifs; RAM, RBPJassociation module; S2, cleavage site 2; S3, cleavage site 3; TAD, transactivation domain. References: 1, Baeten, Jackson, McHugh, and Lilly (2015); 2, Baeten and Lilly (2015); 3, Beckers, Clark, Wunsch, Hrabe De Angelis, and Gossler (1999); 4, Boucher, Harrington, Rostama, Lindner, and Liaw (2013); 5, Domenga et al. (2004); 6, High et al. (2007); 7, Joutel et al. (2000); 8, Kofler et al. (2015); 9, Li, Takeshita, et al. (2009); 10, Lindner et al. (2001); 11, Liu, Zhang, Kennard, Caldwell, and Lilly (2010); 12, Luo, Aster, Hasserjian, Kuo, and Sklar (1997); 13, Manderfield et al. (2012); 14, Shutter et al. (2000); 15, Sweeney et al. (2004); 16, Varadkar et al. (2008); 17, Villa et al. (2001); 18, Wang, Zhao, Kennard, and Lilly (2012); 19, Wang, Pan, Moens, and Appel (2014); 20, Wu et al. (2005).

Fig. 2

Notch signaling pathway. (1) Notch receptor and ligand genes are transcribed and translated into protein. (2) During posttranslational processing in the Golgi, Notch receptors are cleaved by furin to create heterodimers; both ligands and receptors are glycosylated on their EGF-like repeats by Fringe family enzymes. (3) trans activation of Notch receptor by Notch ligand from a neighboring cell, triggering cleavage by ADAM10 at S2 and γ-secretase at S3, releasing the NICD. (4) cis inhibition of Notch receptor by Notch ligand on the same cell, preventing activation. (5) Endocytosis of Notch ligand with associated NECD can be degraded by the proteasome or recycled back to the cell surface. (6) NICD is shuttled to the nucleus where it binds to RBPJ, displacing HDACs and corepressors such as CIR and recruiting MAML to activate transcription of Notch target genes. (7) NICD can both directly interact with Ras and promote ERK phosphorylation, though the mechanism is not yet known. (8) NICD can bind to the Wnt signaling mediator β-catenin and target it for degradation in the lysosome. (9) Transcription of some genes, including smooth muscle contractile genes, is coregulated by NICD/RBPJ and the TGFβ transcription factor SMAD3. (10) Many signaling pathways can regulate expression of Notch components, including PDGFRβ signaling via the MAPK pathway.