Abstract
BackgroundThe concept of specifying positional information in the adult cardiovascular system is largely unexplored. While the Hox transcriptional regulators have to be viewed as excellent candidates for assuming such a role, little is known about their presumptive cardiovascular control functions and in vivo expression patterns.ResultsWe demonstrate that conventional reporter gene analysis in transgenic mice is a useful approach for defining highly complex Hox expression patterns in the adult vascular network as exemplified by our lacZ reporter gene models for Hoxa3 and Hoxc11. These mice revealed expression in subsets of vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) located in distinct regions of the vasculature that roughly correspond to the embryonic expression domains of the two genes. These reporter gene patterns were validated as authentic indicators of endogenous gene expression by immunolabeling and PCR analysis. Furthermore, we show that persistent reporter gene expression in cultured cells derived from vessel explants facilitates in vitro characterization of phenotypic properties as exemplified by the differential response of Hoxc11-lacZ-positive versus-negative cells in migration assays and to serum.ConclusionThe data support a conceptual model of Hox-specified positional identities in adult blood vessels, which is of likely relevance for understanding the mechanisms underlying regional physiological diversities in the cardiovascular system. The data also demonstrate that conventional Hox reporter gene mice are useful tools for visualizing complex Hox expression patterns in the vascular network that might be unattainable otherwise. Finally, these mice are a resource for the isolation and phenotypic characterization of specific subpopulations of vascular cells marked by distinct Hox expression profiles.
Highlights
The concept of specifying positional information in the adult cardiovascular system is largely unexplored
Distinct Hoxc11- and Hoxa3-lacZ expression patterns in adult blood vessels We previously reported that transgenic mice (n = 4 founders) carrying a Hoxc11-lacZ reporter gene construct in which E.coli lacZ with SV40 RNA processing signals was fused in-frame to Hoxc11 exon 1 coding sequences exhibited a conspicuous and reproducible β-gal expression pattern in mid-gestation embryos at ≈ E12 [25]
FVaigliudarteio5n of endogenous Hoxa3 expression boundary in adult carotid artery of FVB/NTac mouse Validation of endogenous Hoxa3 expression boundary in adult carotid artery of FVB/NTac mouse. (A) Diagram of right carotid segment indicating reporter gene expression domain with anterior boundary at level of lingual artery as observed in Hoxa3-lacZ transgenic mouse; yellow arrow points to carotid bifurcation into internal and external carotid arteries, respectively; sections corresponding to levels L1 and L2 as indicated in the cartoon were used for detection of Hoxa3 and Acta2 by immunofluorescence as shown in the three upper (B,B'B") and lower (C,C',C") panels to the right
Summary
The concept of specifying positional information in the adult cardiovascular system is largely unexplored. The Hox transcriptional regulators are known to play a critical role in establishing positional identities during embryonic patterning [1], whereas in postnatal and adult tissues, their functions are largely subject to speculation [2]. This pertains to the adult cardiovascular system, Hox genes are considered prime candidates for determining phenotypic characteristics of vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) during vasculogenesis and vascular remodeling both under normal (e.g. wound healing, menstrual cycle) and pathologic conditions (e.g. cancer-related angiogenesis, atherosclerosis) [3]. Perhaps of equal relevance is that in the fruit fly Drosophila melanogaster the Hox gene abdA is required for specifying cell identity in a posterior section of the Drosophila dorsal vessel, which is functionally equivalent to the vertebrate heart [7]
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