Heart Wall - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 277

Tabl e 6. 3. Factors of cardiac valve development and remodeling (Source: [ 485 ]). Various
signaling pathways and transcriptional regulators coordinately regulate valvulogenesis (BMP:
bone morphogenetic protein; HA: hyaluronic acid; HAS: hyaluronan synthase; HBEGF: heparin-
binding epidermal growth factor-like growth factor; HER: human epidermal growth factor
receptor; NF1: neurofibromin-1; NFAT: nuclear factor of activated T cells; TGF: transforming
growth factor; VEGF: vascular endothelial growth factor).

Factor Effect

BMP2/4/6 Epithelial-mesenchymal transition

HA Epithelial-mesenchymal transition, migration

via HER2 and HER3

HBEGF Inhibition of cell proliferation

NF1 Inhibition of Ras GTPase (of cell proliferation)

Notch TGF β signaling

TGF β Cell mobilization

VEGF Endothelial cell proliferation via NFAT2

Wnt Production of BMP4, versican, HAS2

phosphatase-3 [ 485 ]. Phosphatase PP3, in turn, dephosphorylates NFAT2 that then
moves into the nucleus, where it interacts with transcriptional regulators such as
Activator protein-1 to trigger gene transcription.
Activated Notch is converted from a transmembrane receptor to a transcriptional
coactivator that participates in the control of epithelial-mesenchymal transition of
endocardial cushions. Notch signaling increases the level of transforming growth
factor- 2. The latter increases the activity of Snail transcription factor, thereby

downregulating cadherin-5 and endothelial cell separation. On the other hand,
SMAD6 attenuates TGF

β

β signaling in developing valves [ 485 ].

The major TGF β family members implicated in cardiogenesis include TGF β 2,

TGF 3 is synthesized in

transforming endothelial and invading mesenchymal cells, whereas bone morpho-
genetic protein-2 is expressed in the myocardium. Myocardial signals upregulate
the expression of endothelial TGF

β 3, BMP2, and BMP4 factors. Transforming growth factor- β

3 that acts synergistically with BMP2 in
the atrioventricular canal to prime the epithelial-mesenchymal transition [ 498 ].
The production of BMP2 and BMP4 is stronger in the myocardium underlying
developing atrioventricular canal and outflow tract, respectively. Isotype BMP6 is
expressed in endocardium, myocardium, and mesenchyme of the developing heart,
especially in the atrioventricular canal [ 485 ].
Heparin-binding epidermal growth factor-like growth factor (HBEGF) is strongly
expressed in the endocardium overlying the cushion-forming area. It is cleaved
from the transmembrane precursor proHBEGF by ADAM17 metallopeptidase.
It can bind human epidermal growth factor receptors HER1 and HER4. It limits
mesenchymal cell proliferation once bound to HER1-HER2 heterodimer [ 485 ].
On the other hand, activation of HER2-HER3 heterodimer by hyaluronic
acid increases the epithelial-mesenchymal transition and migration via Ras sig-
naling [ 485 ]. Hyaluronic acid is produced by hyaluronan synthases (HAS1-
HAS3). Enzyme HAS2, the main enzyme for hyaluronic acid production during

β