Smooth Myocytes - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 410

Intimal hyperplasia is characterized by a temporospatial change in Notch-1 to
Notch-3 activity [ 752 ]. In smooth myocytes, Notch-1, but not Notch-3, mediates
proliferation, migration, and survival, hence neointima formation.
Pulmonary arterial hypertension results from a remodeling of small pulmonary
arteries with proliferation of smooth muscle and endothelial cells that causes wall
thickening and lumen narrowing. The Notch-3-HES5 pathway is involved [ 752 ].
Platelet-derived growth factor-BB and transforming growth factor- mediate

vSMC phenotype switching. The former is involved in the repression of vSMC-
specific gene expression; the latter promotes the contractile phenotype. Notch
cooperates with PDGF and TGF

β

to regulate vSMC migration and differentia-
tion [ 745 ]. On the other hand, Wnt inhibitory factor-1 hampers PDGFbb-induced
vSMC proliferation.

β

8.5.3.4 Wnt Signaling in vSMC Specification

Secreted, cysteine-rich Wnt glycoproteins that are encoded by 19 genes regulate
SMC proliferation, differentiation, migration, and survival. They interact with
10 Frizzled receptors as well as coreceptors, such as low-density lipoprotein-related
proteins LRP5 and LRP6 for the canonical,

-catenin dependent Wnt pathway
and receptor protein Tyr kinase-like orphan receptor ROR2 for the non-canonical,
β

β

-catenin independent Wnt axis.
Wnt proteins regulate the synthesis of several matrix constituents, such as
fibronectin and versican, as well as matrix metallopeptidases (MMP2, MMP3,
MMP7, MMP9, MMP13, MMP14, and MMP26).
In the conventional pathway,

-catenin translocates to the nucleus, where it as-
sists in the TCF-LEF-mediated transcription of target genes. In arterial and venous
smooth myocytes, the

β

Ctn-TCF axis upregulates cyclin-D1 and downregulates
CKI1a cyclin-dependent kinase inhibitor, thus increasing the proliferative rate.
Wnt1 and Wnt3a can trigger cyclin-D1 production in arterial smooth myocytes in
vitro. Under growth factor stimulation, Wnt4 supports arterial SMC proliferation in
vitro; it also contributes to pathological intimal thickening in vivo [ 753 ].
In unconventional pathways, Wnts initiate the PLC-Ca 2 + axis, thereby activating
via calmodulin CamK2 and PP3 that stimulate NF

β

κ B and NFAT transcription factors

on the one hand and PKC that stimulates NF B and CREB transcription factors on

the other. Furthermore, Wnt can bind to ROR2 in the absence of Frizzled to release
Ca 2 + from intracellular stores and activate JNK kinase. In addition, Wnt can also
activate Rho and Rac GTPases, hence RoCK on the one hand, and PKA, thus CREB
on the other. Factor NFAT1 promotes cyclin-D1 gene expression, hence arterial
SMC proliferation [ 753 ]. In addition, CamK2 favors arterial SMC proliferation.
Moreover, JNK is activated in proliferating smooth myocytes.

κ