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Prepublished online as a Blood First Edition Paper on August 1, 2002; DOI 10.1182/blood-2002-03-0955.
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Blood, 1 December 2002, Vol. 100, No. 12, pp. 4019-4025
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Differential regulation of the von Willebrand factor and Flt-1
promoters in the endothelium of hypoxanthine
phosphoribosyltransferase-targeted mice
Takashi Minami,
Diana J. Donovan,
Jo C. Tsai,
Robert D. Rosenberg, and
William C. Aird
From the Department of Molecular Medicine, Beth Israel
Deaconess Medical Center, Boston, MA.
An important limitation of standard transgenic assays is that
multiple copies of the transgene are inserted randomly into the mouse
genome, resulting in line-to-line variation in expression. One way to
control for these variables is to target a single copy of the transgene
to a defined locus of the mouse genome by homologous recombination. In
the present study, we have used such an approach to target the
promoters of 2 different genes, namely von Willebrand factor (VWF) and
Flt-1, to the hypoxanthine phosphoribosyltransferase (Hprt) gene locus.
Consistent with previous findings in standard transgenic animals, we
report that the VWF promoter contains information for expression in a
subset of endothelial cells in the heart, skeletal muscle, and brain.
In contrast, the Flt-1 promoter directs expression in all vascular beds
except for the liver. The Flt-1 transgene was active in the endothelium
of tumor xenografts, whereas the VWF promoter was not. Under in vitro
conditions, conditioned medium from tumor cells resulted in a
significant up-regulation of Flt-1 mRNA and promoter activity, but no
change in VWF levels. Taken together, these results suggest that (1)
Hprt locus targeting is a valuable tool for studying vascular
bed-specific gene regulation, (2) the VWF and Flt-1 promoters are
regulated by distinct transcriptional mechanisms in the intact
endothelium, and (3) tumor angiogenesis results in the differential
activation of endothelial cell-specific promoters.
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