Smooth Myocytes - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 409

Smooth myocytes of organ arteries have also diverse origins. The neural crest
gives rise to smooth myocytes and pericytes of most brain vessels; the mesothelium
and proepicardium generate mesenteric and coronary vessels, respectively [ 752 ].
Notch stimulates various aspects of vSMC specification, differentiation, and
maturation during development. Notch positively regulates differentiation of cardiac
neural crest precursor cells into smooth myocytes. Notch is also required in the
second heart field for proper patterning of the outflow tract [ 752 ]. Notch controls
the differentiation of epicardium-derived cells into coronary smooth myocytes.
In classical Notch signaling, the extracellular domain of Notch receptor on the
surface of signal-receiving cells interacts with the extracellular domain of Notch
ligand on apposed signal-sending cells (Vol. 3 - Chap. 10. Morphogen Receptors).
Four Notch receptors (Notch-1-Notch-4) on signal-receiving smooth myocytes
tether to 5 transmembrane Delta-like and Jagged ligands (DLL1, DLL3-DLL4,
and Jag1-Jag2) on apposed signal-sending endothelial and smooth muscle cells.
Notch-1 and Notch-4 reside primarily in endothelial cells; Notch-1 pulmonary artery
smooth myocytes during development; Notch-2 in mesenchymal cells and aorta and
pulmonary artery smooth myocytes; Notch-3 in smooth myocytes and pericytes of
the microvasculature of the central nervous system [ 752 ]. Ligands DLL1, DLL4,
and Jag2 lodge on endothelial cells; Jag1 on both endothelial and smooth muscle
cells. In addition, Notch receptors can interact with other ligand types. 35
Notch receptor is transported to the cell surface as a heterodimer. Notch receptor
precursor is actually cleaved by furin during transport to the plasma membrane
into a large ectodomain (Notch ECD ) and a membrane-tethered intracellular do-
main (Notch MTIC ) that remain connected by a juxtamembrane heterodimerization
domain.
Upon ligand binding, Notch is successively cleaved by adamlysins such as
ADAM17 at the extracellular juxtamembrane region and by the -secretase complex

that liberates the Notch intracellular domain (Notch ICD ) from the plasma membrane.
On the one hand, Notch ECD is endocytosed into the signal-sending cell. On the
other, Notch ICD translocates to the nucleus, where it forms an active transcriptional
complex with RBPJ

γ

transcription factor and coactivators such as Mastermind-like
coactivator (MamL). In the absence of Notch, RBPJ

κ

represses transcription, as it
recruits histone deacetylases and other corepressors. Nuclear Notch ICD

κ

displaces

the histone deacetylase-corepressor complex from RBPJ , enabling transcriptional

activation of Notch target genes such as class-B basic helix-loop-helix proteins
Hairy enhancer of Split (HES1-HES7 or bHLHb37-bHLHb43) and HES-related
transcriptional regulators (HRT1-HRT3). In addition, other Notch target includes
PDGFR

κ

, the microRNA cluster miR143-miR145, and components of the Notch
pathway (e.g., Notch-3 and Jag1).

β

35 In vitro, microfibril-associated glycoproteins MAGP1 and MAGP2, which associate with
fibrillins in elastic fibers, can bind to the extracellular domain of Notch-1 and activate Notch [ 752 ].