Vasculature Growth - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 665

Lymphatic vessel endothelial hyaluronan receptor LyVE1 in endothelial cells that
coat anterior cardinal veins is the first marker of differentiation of blood endothelial
cells into lymphatic endothelial cells [ 1360 ]. The population of LyVE1 endothelial

cells constitutes the first committed lymphatic endothelial cells that migrate from the
cardinal vein to form the primary lymph sacs.

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10.8.1 Transcription Factors in Lymphangiogenesis

Transcription factor prospero-related homeobox gene product Prox1 is required
during initial lymphangiogenesis, i.e., endothelial precursor budding from the car-
dinal vein. Factor Prox1 regulates lymphatic endothelial cell differentiation [ 1361 ].
It indeed causes expression of specific genes of lymphatic endothelial cells and
downregulates those of endothelial cells of blood vessels. It not only targets
homeobox-containing genes, but also interacts with nuclear receptors such as
NR5a2. 89
Developmental transcription factor sex determining region-Y (SRY)-related high
mobility group (HMG) box Sox18 intervenes in lymphatic development [ 1362 ].
Factor Sox18 is expressed in a subset of cardinal vein cells that later coexpress
Prox1, differentiate into lymphatic endothelial cells, and migrate to form lymphatic
vessels. Agent Sox18 activates Prox1 transcription by binding to its proximal
promoter. During later stages of embryonic lymphangiogenesis, Sox18 expression
decreases [ 1363 ]. In fact, Sox18 is not involved in Prox1 production in mature
lymphatic endothelial cells. Homeobox gene product HoxD8 may then maintain
Prox1 synthesis.
Forkhead box factor FoxC2 is involved in the differentiation of terminal and col-
lecting lymphatics, as well as in the formation of valves. Transcription factor FoxC2
is expressed in lymphatic primordia, jugular lymph sacs, lymphatic collectors, and
capillaries [ 1364 ]. Mutations in the FOXC2 gene cause the hereditary lymphedema-
distichiasis syndrome. Factor FoxC2 is implicated in the differentiation between
lymphatic capillaries and collecting, valvular lymphatic vessels. It is required not
only for the formation of lymphatic valves, but also the establishment of pericyte-
free lymphatic capillaries in cooperation with VEGFR3 [ 1365 ]. In FoxC2-deficient
fetuses, lymphatic capillaries are abnormally covered with smooth myocytes and
collecting lymphatic vessels lack valves. In addition, PDGFb and endoglin are
upregulated and deposition of basement membrane collagen-4 rises.
Nuclear receptor NR2f2 is expressed in the venous and lymphatic endothelial
cells [ 1363 ]. It directly activates Prox1 expression in venous lymphatic endothelial
progenitors.
Both Sox18 and NR2f2 synergistically induce the Prox1 expression. Factor
Prox1 downregulates venous blood vessel endothelial cell markers and upregulates

89 A.k.a. liver receptor homolog-1.