**4.10. Hox genes with anti-angiogenic effects**

As previously described, several transcription factors encoded by Hox genes contribute to anti-angiogenic activity such as *HOXA5*, *HOXC9*, and *HOXD10* [79].

these observations suggest that there is an overlapping and complementary role between Hox genes to maintain a balance between pro-angiogenic and anti-angiogenic states (**Figure 3**).

Hox Genes in Adult Tissues and Their Role in Endothelial Cell Differentiation and Angiogenesis

http://dx.doi.org/10.5772/intechopen.76745

39

Hox genes act as transcriptional regulators, which have been involved in the differentiation of stem cells into several lineages and different cell types. One of the main steps to initiate vasculogenesis and angiogenesis is the differentiation to endothelial lineage from pluripotent stem cells. Studies have suggested that Hox genes contribute to the differentiation of EPCs into mature endothelial cells (**Table 1**). In the next section, we will present the evidence for the

Several members of the Hox family play an important role in the embryonic development of the cardiovascular system and regulate angiogenesis in adults [84]. In addition, some Hox transcription factors such as HoxD3, HoxC6, and HoxC8 modulate the expression of proteins in mature endothelial cells, whereas HoxB5 appears to be involved in the in vitro differentiation of embryonic precursor cells toward endothelial lineage [66, 81]. *HoxA9* is important for myeloid, erythroid, and lymphoid hematopoiesis [88, 89] and stem cell expansion [90]. It is also essential for the migration and tube-forming capacity of mature endothelial cells [51] and could serve as a switch toward endothelial commitment during progenitor cell maturation. The *HOXD3* gene is also involved in the differentiation of EPC to endothelial cell. The expression of *HOXD3* retained endothelial cells in an invasive state and prevented vessel maturation leading to vascular malformations and vascular tumors. Therefore, HoxD3 regulates endothelial cell gene expression associated with the invasive stage of angiogenesis. The expression

**Target gene Regulation Functions Reference**

migration

proliferation

activation

vessel formation

[47]

[84]

[53]

uPAR + Endothelial cell

VEGFR2 + Endothelial cell

EphrinB4 + Angiogenesis [51] eNOS + Endothelial cell

MMP-14 +

HoxB3 Neovascularization Ephrin A1 + Endothelial cell

**5. Hox genes and adult stem cells**

**5.1. Endothelial progenitor cells**

**Cellular type Hox** 

*Pro-angiogenic* Endothelial cells of the human dermal microvasculature

Cellular line (MDA-MB-231, T47D,

Endothelial cells of the human dermal microvasculature

MTLn3)

**genes**

HoxB2

HUVECs HoxA9 Post birth

**Period of expression**

HoxA3 Late embryogenesis and wound healing

neovasculogenesis

role of Hox genes in the differentiation of adult stem cell.
