Regulation of the Hox genes in vascular cells.
Abstract
HOX genes belong to a family of transcription factors characterized by a 183 bp DNA sequence called homeobox, which code for a 61-amino-acid domain defined as the homeodomain. These genes play a central role during embryonic development by controlling body organization, organogenesis, and stem cell differentiation. They can also play a role in adult processes such as embryo implantation, hematopoiesis, and endothelial differentiation. Since endothelial cell differentiation is one of the main steps to initiate vasculogenesis and angiogenesis, we analyzed the role of several Hox genes in the regulation of these two processes. In this chapter, we summarized the evidence to support the function of Hox genes in adult tissues, specifically in endothelial cell differentiation, by studying their mechanism of action and how their target genes regulate vasculogenesis and angiogenesis. Understanding the cellular and molecular mechanisms triggered by Hox biological effects is pivotal for designing new drugs or therapies for high prevalent pathologies, such as cardiovascular diseases.
Keywords
- Hox genes
- endothelial cell differentiation
- angiogenesis
- vasculogenesis
- embryonic development
1. Overview
Hox genes are responsible for the expression of a large family of transcriptional factors that play a key role in embryonic development, organogenesis, and anteroposterior body orientation [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.
2. Origin of the Hox gene cluster
The Hox genes were discovered in 1915 by Calvin Bridges in a mutant
3. Hox genes in adult-related processes
3.1. Endometrial tissue
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, 12, 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].
More recently, Yim et al. suggested that
3.2. Implantation
Implantation is a series of sequential biological events triggered after fertilization in which the blastocyst migrates from the fallopian tube into the uterus. The fertilized egg is then attached to the uterine wall and subsequently implanted in the endometrium. Implantation occurs only in a very specific time period and place during the mid-secretory phase of the uterine cycle [24]. During this period, the uterus becomes more receptive by promoting a series of cellular and molecular events favoring the implantation of the embryo. In this stage, the role of several intercellular mediators has been implicated, which include specific cytokines, growth factors, adhesion molecules, lipid mediators, steroid hormones, and Hox transcription factors [25]. Like in endometrial tissue,
3.3. Hematopoiesis
Hox genes are highly expressed in hematopoietic stem cells (HSC) and immature progenitor cells [32]; however, this expression is gradually decreased upon cell differentiation. Moreover, overexpression of genes from the
Another gene involved in this process is
Another Hox gene family member linked to hematopoiesis is
4. Hox genes in vascularity and angiogenesis
The development of the vascular system involves two processes called vasculogenesis and angiogenesis [42]. During vasculogenesis, angioblasts derived from different sources, including mesodermal embryonic layer or bone marrow, differentiate into endothelial cells and subsequently form a primitive network of tubular structures called blood vessels [43]. Vasculogenesis occurs largely during embryonic development; however, the presence of a population of circulating endothelial progenitor cells (EPCs) derived from the bone marrow in adults strongly suggests that this process may occur in the postnatal period [44]. In contrast, angiogenesis refers to the formation of new blood vessels from preexisting vessels by cell migration and remodeling of the primitive vascular network [45]. Vasculogenesis and angiogenesis are involved in the development of the functional vascular system in the embryo and the formation of blood vessels in the postnatal period. Both vasculogenesis and angiogenesis are under the regulation of several growth factors, which include vascular endothelial growth factor (VEGF), fibroblast growth factor 2 (FGF2), platelet-derived growth factor (PDGF), and transforming growth factor β1 (TGF-β1), among others [45]. Interestingly, different research groups have found that Hox genes regulate the expression of these growth factors and, in turn, endothelial cell differentiation. In the next section, we will describe supporting evidence about the role of Hox genes in endothelial differentiation, vasculogenesis, and angiogenesis (Figure 2).
4.1. HOXA3
The
4.2. HOXA9
The
In 2004, Bruhl et al. showed that
4.3. HOXA13
The central function of the placenta is to allow the formation of a vascular labyrinth, a juxtaposed series of finely branched blood vessels and trophoblast that regulate the exchange of nutrients and residues while maintaining the separation of maternal and fetal blood supplies. The study by Shaut et al. showed a morphological alteration in the labyrinth endothelial cells, branching of the vessels, and in the integrity of the vessels when
Besides HoxA genes, the HoxB and HoxD loci have also been involved in endothelial and angiogenesis regulation processes [60]. HUVECs, for example, express several genes from these loci [7], and it has been shown that some of these genes inhibit in vitro proliferation of HUVECs, whereas others have been associated with increased capillary morphogenesis and vasculogenesis [61].
4.4. HOXB1
Previous studies have revealed an overlap between HoxA1 and HoxB1 functions during the specification of the rhombomeres, a transiently divided segment of the developing neural tube, from which neural crest cells emerge. It has been demonstrated that both HoxA1 and HoxB1 functions are required for the heart development [62, 63]. HoxB1−/− embryos were previously described as embryos with normal pharyngeal arch arteries and cardiac neural crest-derived tissue remodeling [64]. However, more recently, Roux et al. observed one HoxB1 mutant embryo with an aortic arch artery defect, which is characteristic of a developmental failure of the left pharyngeal arch arteries (PAA) [65]. These data suggest that
4.5. HOXB3
The function of the
4.6. HOXB5
The
Furthermore, other studies have shown that HoxB5 is a transactivator of the promoter of VEGFR2, an early marker of endothelial precursors [66], which might be involved in the differentiation of mesoderm-derived precursors toward an endothelial phenotype [66, 68]. In fact, it has been described that overexpression of HoxB5 leads to differentiation of mesoderm-derived precursors toward the endothelial phenotype, which in turn lead to high expression of angiopoietin 2 (ANG2) and therefore enhance vascularization in a model of fertilized white Leghorn chicken eggs [68].
4.7. HOXB7
4.8. HOXD1
4.9. HOXD3
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
4.11. HOXA5
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].
4.12. HOXC9
4.13. HOXD10
5. Hox genes and adult stem cells
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 role of Hox genes in the differentiation of adult stem cell.
Cellular type | Hox genes | Period of expression | Target gene | Regulation | Functions | Reference |
---|---|---|---|---|---|---|
Endothelial cells of the human dermal microvasculature | HoxA3 | Late embryogenesis and wound healing | uPAR | + | Endothelial cell migration | [47] |
MMP-14 | + | |||||
HUVECs | HoxA9 | Post birth neovasculogenesis | EphrinB4 | + | Angiogenesis | [51] |
eNOS | + | Endothelial cell proliferation | [84] | |||
VEGFR2 | + | Endothelial cell activation | ||||
Cellular line (MDA-MB-231, T47D, MTLn3) | HoxB2 | |||||
Endothelial cells of the human dermal microvasculature | HoxB3 | Neovascularization | Ephrin A1 | + | Endothelial cell vessel formation | [53] |
Angioblasts (rat) | HoxB5 | Neovascularization | VEGFR2 | + | Endothelial cell activation | [66] |
HUVECs | HoxD3 | Neovascularization | Collagen1A1 | + | Adhesion and migration of endothelial cells | [77] |
Human microvasculature endothelial cells | Integrin-α | + | [78] | |||
Murine embryonic stem cells | HoxA13 | Postnatal neovascularization | EphA4 | + | Organización células endoteliales y formación de vasos | [54] |
EphA7 | + | |||||
Vascular smooth muscle cells | Prx1 | Late embryogenesis | TN-C | + | Proliferation of smooth muscle cells | [85] |
α-Actin | + | [65] | ||||
Vascular smooth muscle cells | Prx2 | Late embryogenesis | TN-C | + | Proliferation of smooth muscle cells | [85] |
Human pulmonary endothelial cells | Hhex | Vascular insult | Myh10 | + | Plasticity smooth muscle cells | [84] |
Human brain endothelial cells | Meox2 | Postnatally | MLL77 | — | Endothelial cell apoptosis | [66] |
HUVECs | HoxA5 | Postnatally | VEGFR2 | – | Endothelial cell activation | [86] |
Ephrin A1 | – | Endothelial cell migration | [87] | |||
Human endothelial cells | HoxD10 | Postnatally | Integrin-α | — | Endothelial cell migration | [53] |
5.1. Endothelial progenitor cells
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].
6. Conclusions
Hox genes have been traditionally recognized as genes involved in the embryonic development; however, further research showed that homeobox genes also play a role as master regulators of tissue and organ patterning in adults. These genes can regulate cell differentiation, proliferation, and migration to tissues exposed to constant turnover, such as vasculature, 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 such as VEGF, IL-8, Efna1, and TSP-2 among other gene targets.
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.
Acknowledgments
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 discussion of the ideas presented in this manuscript.
Source of funding
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).
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