**3.1. Endometrial tissue**

[1, 2]. Even though the main function of these genes is well known during embryogenesis, their role in adults remains under investigation. Several studies have linked Hox genes with adult processes such as vascularization, hematopoiesis, tumor angiogenesis, and cell differentiation [3]. In this chapter, we will focus our attention on the origin and main role of Hox genes in adult tissues, especially on endothelial cell differentiation, neovasculogenesis, and angiogenesis.

The Hox genes were discovered in 1915 by Calvin Bridges in a mutant *Drosophila melanogaster* named Bithorax, which showed a partial duplication of the thorax [4]. Years later, another mutation in the Hox genes was identified resulting in a mutant fly exhibiting legs instead of antenna named Antennapedia [5]. The Hox genes were then grouped into these two complexes (Bithorax and Antennapedia), which are located on chromosome 3 and play a key role in conferring the identity along the anteroposterior axis of the body. The role of these genes in establishing the anteroposterior axis is highly conserved in vertebrates [5, 6]; however, the Hox gene cluster has changed during its evolution, evidenced by different numbers of clusters between species (**Figure 1**). For example, whereas invertebrates typically possess a single cluster, vertebrates such as mice and humans possess four gene clusters coding for the three different axes: cervical, thoracic, and lumbosacral [2, 6]. Despite these differences, Hox genes have been identified in all species, which reflects the important role of these genes in the regulation of body structure [1, 7]. In humans, the 39 mammalian Hox genes are grouped into four chromosomal clusters named *HOXA*, *HOXB*, *HOXC*, and *HOXD*, located on chromosomes 7p14, 17q21, 12q13, and 2q31, respectively [8]. This large family encodes homeodomain transcription factors that share highly conserved DNA sequence formed by 183 bp called "homeobox," which encodes a polypeptide core of 61 amino acids formed by three alpha helices known as the homeodomain. Most homeodomains recognize highly conserved DNA elements that

**Figure 1.** The composition and evolutionary differences of the HOX gene cluster between *Drosophila melanogaster*, mouse, and *Homo sapiens*. The HOX gene clusters and their chromosomal location were compared between *Drosophila melanogaster*, mouse, and *Homo sapiens*. Genes were grouped according to the distribution of the three axes corresponding

to the anteroposterior part of the body (cervical, thoracic, lumbosacral).

**2. Origin of the Hox gene cluster**

30 Endothelial Dysfunction - Old Concepts and New Challenges

Hox genes are crucial during endometrium redevelopment and corpus luteum formation because they regulate cell growth and differentiation during each reproductive cycle [10]. Expression of HoxA10 in human epithelial and stromal endometrial cells has been significantly higher in the intermediate and late phase of the menstrual cycle, suggesting that it could favor the implantation of the embryo [11–13]. Mechanistically, the protein encoded by this gene regulates the expression of several proteins related to endometrial development such as Emx2/EMX2, integrin β3, insulin-like growth factor-binding protein-1 (IGFBP-1), cyclin inhibitors, Wnt family genes, and the prostaglandin receptors EP-3 and EP-4 [14, 15].

Endometrium development is regulated by estrogen and progesterone; thus, any regulation of Hox genes by these hormones suggests that these genes play a role in the growth and development of the endometrium. For example, 17β-estradiol and progesterone significantly increased the expression of HoxA10 in endometrial cells [16] and primary culture of stromal endometrial cells, respectively, with a higher response induced by progesterone compared to 17β-estradiol [17] and even higher when both hormones were used in combination [17, 18].

*HOXA11* is another hox gene from the A cluster that has been closely associated with morphological alterations [19]. During the development of the female reproductive tract, *HOXA11* is normally expressed in the cervix and lower uterine segment. When the expression of this gene is impaired, it promotes aberrant epithelial cell differentiation leading to epithelial ovarian neoplasia [20, 21]. In addition, *HOXA11*−/− mice exhibit reduced development of the stroma in the glandular tissue and decidua during pregnancy [18, 22], suggesting a role in myometrium preparation to implantation.

More recently, Yim et al. suggested that *HOXA11* promotes metastasis by regulating the expression of gene coding for metastasis-related proteins [23]. These findings indicate that *HOXA11* plays a role in the aggressive nature of ovarian cancer cells through *HOXA11* mediated expression of target genes such as matrix metalloproteinase (MMP) and VEGF.
