Vasculature Growth - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 666

specifiers of the lymphatic endothelial cell phenotype. Factor Prox1 collaborates
with ETS2 90 to stimulate VEGFR3 production. On the other hand, NR2f2 and Prox1
cooperate for FGFR3 synthesis; NR2f2 binds to Prox1 factor [ 1363 ].

10.8.2 Growth Factors and Guidance Molecules

Sprouting, growth, survival, migration, and proliferation of lymphatic en-
dothelial cells need vascular endothelial growth factor-C and -D that activate
VEGFR3 [ 1361 ] 91 and neuropilin-2. 92 Neuropilin-2 expressed in lymphatic vessels
can interact with VEGFR3 and bind to lymphangiogenic VEGFc and VEGFd.
Isotype VEGFd is less important than VEGFc isoform. Fibroblast growth factor-
2, platelet-derived growth factor-B, and hepatocyte growth factor also stimulate
lymphatic vessel growth [ 1367 ].
In adult mice, myeloid cells are sources of VEGFc and VEGFd factors. Mono-
cytes M2 that express SYK kinase exhibit a lymphangiogenic activity, as they
stimulate endothelial cell sprouting via VEGFc and VEGFd [ 1368 ]. Factors VEGFc
and VEGFd have essential and modulatory functions, respectively, during lymphan-
giogenesis.
Angiopoietin receptors TIE1 and TIE2 are produced by lymphatic endothelial
cells [ 1369 ]. Receptor TIE2 is expressed at lower levels in lymphatic vessels than
in blood vessels, but Ang2 is synthesized in a greater amount in endothelial cells of
lymph vessels than in blood vessels.
Angiopoietin-1 and VEGF collaborate during blood vessel development.
Angiopoietin-1 activates TIE2 receptor. On the other hand, angiopoietin-2 either
activates or blocks TIE2 according to the cell type [ 1370 ]. Angiopoietin-2 acts as
an agonist in lymphatic vessels and antagonist in blood vessels. Isoforms Ang1
and -2 have a redundant role in lymphatics. Furthermore, angiopoietins bind to
integrins in lymphatic endothelial cells. Angiopoietin-2 is required in patterning
of the lymphatic network and recruitment of smooth myocytes to the collecting
lymphatics.
Ephrin-B2 that signals via EPHb4 is involved in the remodeling of the lymphatic
vasculature and valve formation [ 1371 ]. In the absence of the binding PDZ domain
of ephrin-B2, pericytes and vascular smooth myocytes do not stably associate
with blood vessels, albeit blood vessel defects do not occur. On the other hand,

90 Nineteen ETS transcription factors are expressed in blood vessel endothelial cells.
91 Receptor VEGFR3 exists in all vascular endothelia during embryo- and fetogenesis, whereas
in adults, it is restricted to the lymphatic endothelium. However, VEGFR3 is observed in the
microvasculature of tumors and wound healing. In adult humans, VEGFR3 is also synthesized
in some fenestrated and discontinuous endothelia of blood vessels. Receptor VEGFR3 promotes
the migration and proliferation of lymphatic endothelial cells.
92 Neuropilin-2 is a semaphorin receptor of the nervous system and lymphatic capillaries. Com-
bined inhibition of VEGFR2 and VEGFR3 prevents angiogenesis and tumor growth [ 1366 ].