Heart Wall - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 276

receptor, i.e., the GFR 2-ReT complex, is expressed by cardiac parasympathetic

neurons. Receptor GDNFR

α

2 9 is a glycosylphosphatidylinositol (GPI)-anchored
cell surface receptor for both GDNF and Nrtn that primes activation of ReT receptor.
Neurturin binds preferentially to GDNFR

α

1. 10

α 2 coreceptor compared to GDNFR α

6.1.6 Valvulogenesis

Cardiac cushions protrude from the cardiac jelly and underlying myocardium to
form thin, tapered leaflets with a single endothelial cell layer and a central matrix
with collagen, elastin, and glycosaminoglycans [ 485 ]. Endothelial-mesenchymal
transformation allows the generation of the endocardial cushion, the primordia of
valves, and septa of the heart. The final atrioventricular valves derive from endocar-
dial cushions in atrioventricular canal. The development of ventriculoarterial valves
from the outflow tract relies on a population of neural crest cells from the branchial
arches that migrates to the distal outflow tract and contributes to aortopulmonary
septation. Nevertheless, resident cells of leaflets of all the cardiac valves have an
endothelial origin [ 485 ].
Developing cardiac valves, like other avascular tissues, express transcription
factors, such as sex-determining region Y (SRY)-box Sox9, nuclear factor of ac-
tivated T cells NFAT8, Runt-related transcription factor Runx2, and Msh homeobox
gene product Msx2, as well as growth factors, such as BMP2 and TGF 2.

Numerous signaling axes regulate endothelial proliferation and differentiation in
developing and postnatal heart valves, such as VEGF-NFAT2, Notch-TGF

β

β ,Wnt-

β -catenin, BMP-T β R, HBEGF-HER, and NF1-Ras [ 485 ](Table 6.3 ).

-catenin signaling may control production of the growth factors such
as bone morphogenetic proteins as well as structural elements, such as versican and
hyaluronic acid, that are needed for epithelial-mesenchymal transition [ 485 ].
Vascular endothelial growth factor controls the development of endocardial
cushion and cardiac valve. Subtype VEGF 165 signals via the VEGFR1-VEGFR2-
neuropilin-1 complex on endothelial cells and their effectors, such as inositol
triphosphate, diacylglycerol, extracellular signal-related kinases, and, in valve
endothelial cells, transcription factor NFAT2 (or NFATc1) [ 497 ]. Factor VEGF
acts via VEGFR2 and promotes NFAT2 nuclear localization to increase the pro-
liferation of valvular endothelial cells. In addition to Ca 2 + release from its store
upon IP 3 stimulation, Ca 2 + may enter endothelial cells in developing cardiac
cushions through connexin-45-based hexameric gap junctions and activate protein

The Wnt- β

9 A.k.a. GFR

2 and ReTL2.
10 A.k.a. GFR α 1 and ReTL1. Coreceptor GDNFR α 1 binds to GDNF tightly to form a membrane-
associated complex that then interacts with ReT. On the other hand, GDNFR

α

α

2 forms a high-

affinity complex with GDNF or Nrtn only in the presence of ReT [ 496 ].