Topographic patterns of vascular disease: HOX proteins as determining factors?

Abstract

Steadily increasing evidence supports the idea that genetic diversities in the vascular bed are, in addition to hemodynamic influences, a major contributing factor in determining region-specific cardiovascular disease susceptibility. Members of the phylogenetically highly conserved Hox gene family of developmental regulators have to be viewed as prime candidates for determining these regional genetic differences in the vasculature. During embryonic patterning, the regionally distinct and precisely choreographed expression patterns of HOX transcription factors are essential for the correct specification of positional identities. Apparently, these topographic patterns are to some degree retained in certain adult tissues, including the circulatory system. While an understanding of the functional significance of these localized Hox activities in adult blood vessels is only beginning to emerge, an argument can be made for a role of Hox genes in the maintenance of vessel wall homeostasis and functional integrity on the one hand, and in regulating the development and progression of regionally restricted vascular pathologies, on the other. Initial functional studies in animal models, as well as data from clinical studies provide some level of support for this view. The data suggest that putative genetic regulatory networks of Hox-dependent cardiovascular disease processes include genes of diverse functional categories (extracellular matrix remodeling, transmembrane signaling, cell cycle control, inflammatory response, transcriptional control, etc.), as potential targets in both vascular smooth muscle and endothelial cells, as well as cell populations residing in the adventitia.

Keywords: Hox, Blood vessel, Cardiovascular disease, Positional identity, Endothelial cell, Vascular smooth muscle cell

Core tip: Accumulating evidence indicates regionally restricted HOX expression patterns in the adult arterial tree that may reflect a topographic vascular HOX code for specifying positional identities in various cell types of the circulatory system. We propose that this positional information is critical for maintaining local vessel wall homeostasis and that its disruption plays an important role in the development of vascular diseases with distinct topographic preferences. This editorial discusses emerging molecular data in support of this novel concept.