**5.1. Endothelial progenitor cells**

**Figure 3.** HOX genes regulate angiogenesis. Differential expression of Hox genes tightly regulates endothelial cell proliferation, migration, adhesion, and blood vessel formation (angiogenesis) by activating or silencing relevant target genes, such as fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), platelet factor 4 (PF4) or chemokine (C-X-C motif) ligand 4 (CXCL4), interleukin-8 (IL-8), integrin beta 1 (ITGβ1), and both vascular endothelial

As previously described, several transcription factors encoded by Hox genes contribute to

It has been shown that the presence of HoxA5 was associated with the upregulation of thrombospondin-2 (TSP-2), a naturally occurring inhibitor of angiogenesis. In addition, HoxA5 expression was also associated with downregulation of pro-angiogenic genes such as Ephrin A1 (Efna1), VEGFR2, hypoxia-inducible 1α (HIF1α), and cyclooxygenase-2 (COX-2) [80].

*HOXC9* is a transcription factor expressed in blood vessels in mice [81] and in the cardinal vein of zebrafish [82]. Kroll's group investigated this transcription factor in human vascular endothelial cells and zebrafish, and they observed that this protein was a negative regulator of circulating endothelial cells. They found that HoxC9 was highly expressed in resting endothelial cells; however, its expression was downregulated under hypoxic conditions, and overexpression of this factor inhibited endothelial migration, tube formation, and endothelial cell proliferation by targeting IL-8 transcription [82]. Finally, using a zebrafish model, they observed in vivo that HoxC9 overexpression inhibited the development of their vascular structure; this defect was rescued with exogenous IL-8. This data suggests that HoxC9 plays a negative role in the induction of endothelial cell growth by inhibiting IL-8 production [81, 82].

*HOXD10* is another negative regulator gene for angiogenesis as its overexpression inhibited dermal microvascular endothelial cell migration in vitro [53]. In addition, it has been shown that HoxD10 reduces the expression of GATA-binding protein transcription factor, a family of transcription factors that contain two zinc finger motifs and bind to the DNA sequence (A/T) GATA(A/G), from where it acquires its name. HoxD10 via those transcription factors is able to regulate expression of VEGFR1 and VEGFR2 in differentiated endothelial cells [83]. Therefore,

anti-angiogenic activity such as *HOXA5*, *HOXC9*, and *HOXD10* [79].

growth factor receptors 1 and 2 (VEGFR1/VEGFR2).

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

38 Endothelial Dysfunction - Old Concepts and New Challenges

**4.11. HOXA5**

**4.12. HOXC9**

**4.13. HOXD10**

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



endometrium, and bone marrow. Thus, it has been shown that Hox genes can play a role in defining an endothelial phenotype and/or promoting neovascularization; however, other genes from the Hox family can also play an anti-angiogenic role by preventing angiogenesis. These genes regulate different processes by targeting key proteins related to angiogenesis

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

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

41

Since Hox genes play a role in the regulation of stem cell differentiation into endothelium, angiogenesis, and vasculogenesis, the manipulation of these genes could lead to a useful gene therapy in patients with vascular damage. A better understanding of the cellular and molecular mechanisms related to the biological effects of Hox genes is essential for designing new drugs and treatment to treat worldwide prevalent diseases such as cancer and cardiovascular disease.

We would like to thank the research staff of the Vascular Physiology Laboratory, the Group of Investigation in Tumor Angiogenesis (GIANT) from the University of Bio Bio, and the Group of Research and Innovation in Vascular Health (GRIVAS Health) for the outstanding discus-

C.A. is funded by PCI N° PII20150053, and Dirección de Investigación, Universidad de Concepcion (DIUC 211.072.034-1.0), Chile, and Convenio de Desempeño, Universidad de Concepcion, UCO1201. C.E. is funded by Fondecyt Regular 1140586, Fondequip EQM140104, DIUBB 166709 3/R, and GI 171709/VC. E.N-L. is funded by CONICYT—Fondecyt de Iniciacion (Grant Number: 11170610) and Programa de Atracción e Inserción (Grant Number: 79170073).

1 Department of Clinical Biochemistry and Immunology, Faculty of Pharmacy, University of

2 Department of Pharmacology, Faculty of Biological Sciences, University of Concepcion,

3 Vascular Physiology Laboratory, Group of Investigation in Tumor Angiogenesis (GIANT),

4 Group of Research and Innovation in Vascular Health (GRIVAS Health), Chillan, Chile

, Katherine Oporto<sup>1</sup>

, Carlos Escudero3,4 and Claudio Aguayo1,4\*

, Paula Guzmán<sup>1</sup>

,

, Valeria Aguilera<sup>1</sup>

Department of Basic Sciences, University of Bio-Bio, Chillan, Chile

, Felipe Zúñiga1

\*Address all correspondence to: caguayo@udec.cl

such as VEGF, IL-8, Efna1, and TSP-2 among other gene targets.

**Acknowledgements**

**Source of funding**

**Author details**

Valeska Ormazábal<sup>2</sup>

Concepcion, Chile

Concepcion, Chile

Estefanía Nova-Lampeti1

sion of the ideas presented in this manuscript.

uPAR, urokinase receptor; MMP-14, matrix metalloproteinase-14; EhB4, ephrin type-B receptor 4; eNOS, endothelial nitric oxide synthase; VEGFR2, vascular endothelial growth factor receptor 2; Myh10, myosin heavy chain 10; MLL, histone-lysine N-methyltransferase; HUVEC, human umbilical vein endothelial cell.

**Table 1.** Regulation of the Hox genes in vascular cells.

of HoxD genes has been shown to be temporally regulated as the expression of HoxD10 is maximal 3 days after stimulation with angiogenic factors, whereas the expression of HoxD3 increases after 3 days, indicating that the differentiation and maturation of endothelial cells work alongside with changes in the expression of Hox genes [90].
