Hormone replacement therapies (HRT) composed of a combined estrogen and progestin treatment program cause an increased risk of cardiovascular disease. Data suggests that PR is involved in regulation of endothelial-endothelial cell junction, vascular permeability and endothelial cell (EC) proliferation. These data were obtained using a mouse strain that systemically lacks PR function. Using the Cre-loxP site-specific recombination system we are generating a transgenic mouse line carrying a fluxed allele of the murine progesterone receptor (PRIox). Homozygous PRIox mice will be crossed to transgenic mice that express the bacteriophage P1 Cre recombinase in a tissue-specific manner, to generate offspring that lack PR function in specific cell types. In particular, we will cross PRIox mice to strains that express Cre recombinase in ECs (VE-cadherin-Cre) or in smooth muscle cells (SMMHC-Cre). The offspring of these matings will produce animals that specifically lack PR in ECs or smooth muscle cells (SMCs), and allow us to evaluate the effects of PR loss-of-function in these defined vascular cell types in an otherwise wild-type background, as well as to an overexpressor of PR in the endothelium (already existent in the lab). The functional effects of PR in vasculature will be assessed using histology, standard techniques to measure vascular permeability and by evaluation of the ability of the mutant vasculature to support tumor-induced angiogenesis. In parallel, in vitro approaches will be used to ascertain the effect of progesterone signaling at a cellular level. We expect these studies to lead to an improved understanding of PR function in vascular homeostasis and pathological angiogenesis.
