The dual roles of homeobox genes in vascularization and wound healing

Abstract

Homeobox genes represent a family of highly conserved transcription factors originally discovered to regulate organ patterning during development. More recently, several homeobox genes were shown to affect processes in adult tissue, including angiogenesis and wound healing. Whereas a subset of members of the Hox-family of homeobox genes activate growth and migration to promote angiogenesis or wound healing, other Hox genes function to restore or maintain quiescent, differentiated tissue function. Pathological tissue remodeling is linked to differential expression of activating or stabilizing Hox genes and dysregulation of Hox expression can contribute to disease progression. Studies aimed at understanding the role and regulation of Hox genes have provided insight into how these potent morphoregulatory genes can be applied to enhance tissue engineering or limit cancer progression.

Figure 1. Mammalian Hox clusters. Thirty-nine Hox genes are arranged into four distinct chromosomal loci. During human development Hox genes are activated in a 3′ to 5′ manner within each cluster, concomitant with the development of the anteroposterior axis; Hox gene activation is color-coded based approximately on anatomical location during development. Note the presence of two miRNA families (MIR10 and MIR196) within the Hox clusters, which target many Hox genes and may contribute to the posterior prevalence phenomenon.

Figure 2. Hox gene control of the angiogenic switch. Differential expression of Hox genes is key in transitioning between homeostasis and angiogenesis. During homeostasis, HOXA5 and HOXD10 upregulate anti-angiogenic cytokines and inhibit pro-angiogenic signals, thereby maintaining a quiescent endothelial phenotype. Tumor cells can initiate an angiogenic response as a result of a change in Hox gene expression. Loss of HOXA5 and HOXD10 expression (along with the upregulation of HOXB7 and HOXB9) leads to the secretion of pro-angiogenic and pro-inflammatory cytokines. Responsive ECs subsequently downregulate the expression of HOXD10 and upregulate the expression of HOXA3 and HOXD3, thereby assuming an invasive phenotype. Tumor-associated endothelium maintains this invasive phenotype, whereas normal angiogenesis is an ordered process that concludes with a closed capillary network. ECs undergoing capillary morphogenesis express HOXA9 and HOXB3 and are phenotypically distinct from their invasive counterparts.