Vascular Endothelium - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 479

On the other hand, the decoy receptor VEGFR1 limits tip cell formation;
Delta-like ligand DLL4 of Notch receptor prevents tip cell fate in endothelial
cells adjacent to tip cells [ 886 ]. In addition, Roundabout homolog Robo4, and
Wnt signaling in stalk cells repress tip cell behavior to maintain the hierarchical
organization of sprouting endothelial cells.
Vascular tubulogenesis is initiated by the acquisition of the apicobasal polarity
of endothelial cells that is regulated by cell-matrix interactions and signaling via
partitioning defective protein PAR3 and VEGFR receptor [ 886 ].

9.5.3.6 TGF β Receptors

Endothelial cells produce receptor protein Ser/Thr kinases T R1 (or ALK5),

and ALK1 activin receptor-like kinase. Unlike inhibition in quiescent endothelium
of cadherin-5 on the VEGF-ERK1/2 pathway, cadherin-5 at adherens junctions that
is stimulated by TGF

β R2, T β

β recruit T β R2 and enhance the assembly of T β R2-TGF β R1

heteromers [ 887 ].
Activated R1 phosphorylates receptor-associated SMAD proteins

(rSMAD). Receptors ALK1 and ALK5 phosphorylate SMAD1, SMAD5, and
SMAD8

TGF β

and SMAD2 and SMAD3, respectively. Cadherin-5 is needed for

potent, sustained phosphorylation of SMAD1/5 and SMAD2/3 by T R1 receptor.

Phosphorylated cytoplasmic rSMAD dissociates from the receptor and complexes
with SMAD4 mediator. The rSMAD-SMAD4 complex accumulates in the
nucleus and interacts with specific DNA-binding proteins to regulate transcription.
Antiproliferative and antimigratory signaling by TGF

β

thus contributes to Cdh5-
dependent stabilization and remodeling of the vascular endothelium. Activation by
SMAD2 and SMAD3 is indeed stronger than SMAD1 and SMAD/5 stimulation.
Consequently, the TGF

β

β -ALK5-SMAD2/3 pathway is more efficient than TGF β -

ALK1-SMAD1/5/8 signaling that promotes cell growth and motility.
Proliferating endothelial cells synthesize a large amount of endoglin, a modulator
of ALK1 and ALK5, which is bound by TGF . Lack in endoglin or ALK1

causes defects in cardiovascular development. In particuler, endothelial cells of the
endocardium do not undergo mesenchymal transition required for their migration
into the atrioventricular cushion.
Vascular endothelial cells can transform into multipotent stem-like cells us-
ing ALK2 receptor [ 888 ]. Constitutively active ALK2 (upon mutations of the
Alk2 gene) in endothelial cells or exposure to its ligands TGF

β

2orBMP4
causes endothelial-to-mesenchymal transition and acquisition of a stem cell-like
phenotype. These mesenchymal stem-like cells can differentiate into osteoblasts,
chondrocytes, and adipocytes. 33

β

33 Mesenchymal tissues comprise bone, cartilage, muscle, and tendon.