Vasculature Growth - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 627

Class-3 Hox factors (i.e., associated with 3 clusters, HoxA3, HoxB3, and HoxD3)
have a pro-angiogenic role. Thay can provoke endothelial cell migration. Class-
4 Hox factors (HoxA4-HoxD4) are involved in hematopoesis. Factor HoxB5
upregulates VEGFR2 receptor [ 1221 ]. In addition, in vitro, HoxB5 enhances en-
dothelial cell sprouting and modulates the expression of adhesion molecules [ 1221 ].
Nevertheless, HoxB5 may mainly regulate intussusceptive vascular growth. In vivo,
HoxB5 can upregulate angiopoietin-1 and -2 and VEGF [ 1221 ]. Its pro-angiogenic
effect is abolished by soluble TIE2 (TIE2 S ), an angiopoietin antagonist. Factor
HoxB5 also promotes the production of matrix metallopeptidase-1 and -2, but
downregulates that of cell adhesion molecules such as

β 3-integrin.

10.6.2.3 DLx and NKx Factors

Brain development relies on concomitant vasculature development. In mice, te-
lencephalic angiogenesis is governed by a time and space (ventrodorsal) gradient
determined by compartment-specific homeobox transcription factors Distal-less
homeobox protein DLx1 and DLx2, NK2 transcription factor-related homeobox
protein NKx2-1, and paired box protein Pax6 [ 1222 ]. These transcription factors
also regulate the development of telencephalic neuroepithelial domains and neurons.
Factor NKx2-1 is stimulated by sonic Hedgehog that influences both neurogenesis
and angiogenesis. Distal-less homeobox DLx1 and DLx2 hamper the expression
of Delta-like ligand-1, a Notch ligand. Paired box protein Pax6 hinders cornea
vascularization.

10.6.2.4 ETV6 Transcriptional Repressor

Transcriptional repressor ETS-related translocation variant ETV6 34 is needed for
sprouting of human endothelial cells. Factor ETV6 binds to the corepressor
C-terminal-binding protein [ 1223 ]. The ETV6-CTBP complex temporally restricts
VEGF-mediated pulse of Notch ligand DLL4. Control of DLL4 expression, which
depends on the ETV6-CTBP complex, by VEGF is not iterated when VEGF
signals continuously. Whereas VEGFR activation stimulates angiogenesis, Notch
signaling primed by DLL4 inhibits the process. In endothelial cells, VEGF induces
expression of DLL4 that then triggers the Notch pathway in adjacent cells to
attenuate VEGFR activity and prevent spontaneous sprouting in the absence of
sufficient VEGF signaling. The ETV6-CTBP complex further controls branching
by regulating expression of other factors that limit angiogenesis, such as Sprouty
family members and VE-cadherin.

34 A.k.a. translocation ETS leukemia protein (Tel or Tel1) and malignant proliferation, eosinophil
(MPE).