Controlled hypertension, a transgenic toggle switch reveals differential mechanisms underlying vascular disease

A novel inbred rat model with inducible hypertension has been generated usi ng a renin transgene under the transcriptional control of the cytochrome P4 50, Cyp1a1 promoter. The degree and duration of hypertension are regulated tightly by administration of the natural xenobiotic indole-3 carbinol and c an be readily reversed. Induction experiments reveal distinct temporal and mechanistic responses to hypertensive injury in different vascular beds, wh ich is indicative of differential susceptibility of organs to a hypertensiv e stimulus. The mesentery and heart exhibited the greatest sensitivity to d amage, and the kidney showed an adaptive response prior to the development of malignant hypertensive injury. Quantitative analysis of morphological ch anges induced in mesenteric resistance arteries suggest eutrophic remodelin g of the vessels. Kinetic evidence suggests that locally activated plasma p rorenin may play a critical role in mediating vascular injury. This model w ill facilitate studies of the cellular and genetic mechanisms underlying va scular injury and repair and provide a basis for the identification of nove l therapeutic targets for vascular disease.