Interpreting Inflammation Smooth Muscle Positional Identity and Nuclear Factor-κB Signaling

More than a decade ago, DeBakey and Glaeser1 reported that human atherosclerotic lesions form and progress in distinct regional patterns in spite of uniform systemic risk factors, such as smoking, high blood pressure, and serum cholesterol. The authors proposed that this might be because of unknown position-specific genetic differences within the arterial system itself. The Hox gene family is a prime candidate for determining these postulated genetic differences, because these conserved developmental control genes are known to specify positional identities and regional diversities along the longitudinal body axis during embryonic patterning in bilateral animals.2,3 The mammalian Hox system includes 39 genes that are organized in 4 separate clusters designated Hoxa through – d , whose sequence alignment reveals the existence of 13 paralogous Hox groups.4 The successive activation of these tandemly arranged genes in each cluster mirrors the rostro-caudal morphogenetic progression such that the genes located at the 3′ end (groups 1 and 2) are activated first and exhibit the most anterior expression boundaries, and the genes located at the 5′ end (group 13) are activated last and occupy the most posteriorly restricted expression domain. This results in distinct domains of unique combinatorial Hox activities, the so-called Hox code that specifies positional identity at a given location,5 and is believed to function analogous to a postal ZIP code.6 Importantly, this topographical Hox code is retained in certain cell populations of adult tissues, such as dermal fibroblasts, where it is believed to be critical for regulating local differentiation and signaling events.6 See accompanying article on page 1248 Although many Hox genes are reported to be expressed in endothelial cells and vascular smooth muscle cells …