Controlled Hypertension, a Transgenic Toggle Switch Reveals Differential Mechanisms Underlying Vascular Disease

doi:10.1074/jbc.M103296200

Controlled Hypertension, a Transgenic Toggle Switch Reveals Differential Mechanisms Underlying Vascular Disease*

From the ^‡Molecular Physiology Laboratory, University of Edinburgh Medical School, Wilkie Building, Teviot Place, Edinburgh EH8 9AG, United Kingdom, the ^¶Department of Pathology, University of Edinburgh Medical School, Teviot Place, Edinburgh, EH8 9AG, United Kingdom, the ^‖Department of Pharmacology, University of Heidelberg, D-69120 Heidelberg, Germany, the ^**Department of Histopathology, University of Wales College of Medicine, Health Park, Cardiff CF4 2XU, United Kingdom,^‡Institute of Biomedical and Life Sciences, West Medical Building, University of Glasgow, G12 8QQ, United Kingdom, and the ^§§Department of Bio-Medical Sciences, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh EH8 9DX, United Kingdom

Abstract

A novel inbred rat model with inducible hypertension has been generated using a renin transgene under the transcriptional control of the cytochrome P450, Cyp1a1promoter. The degree and duration of hypertension are regulated tightly by administration of the natural xenobiotic indole-3 carbinol and can be readily reversed. Induction experiments reveal distinct temporal and mechanistic responses to hypertensive injury in different vascular beds, which is indicative of differential susceptibility of organs to a hypertensive stimulus. The mesentery and heart exhibited the greatest sensitivity to damage, and the kidney showed an adaptive response prior to the development of malignant hypertensive injury. Quantitative analysis of morphological changes induced in mesenteric resistance arteries suggest eutrophic remodeling of the vessels. Kinetic evidence suggests that locally activated plasma prorenin may play a critical role in mediating vascular injury. This model will facilitate studies of the cellular and genetic mechanisms underlying vascular injury and repair and provide a basis for the identification of novel therapeutic targets for vascular disease.

Footnotes

↵* This work was supported by the Wellcome Trust, the British Heart Foundation, the Deutsche Stiftung fuer Herzforschung, the Biotechnology and Biological Science Research Council, and the Commission of European Communities Concerted Action Program “Transgeneur.”The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
↵§ Supported by a Thai government Ph.D. scholarship and the Faculty of Medicine (Ramathibodi Hospital, Mahidol University, Bangkok, Thailand), where he is presently working.
↵¶¶ Recipient of a Wellcome Trust Principal Research Fellowship. To whom correspondence should be addressed. Tel.: 44-131-6511620; Fax: 44-131-6511594; E-mail: J.Mullins@ed.ac.uk.
Published, JBC Papers in Press, July 11, 2001, DOI 10.1074/jbc.M103296200
Abbreviations:

MH

malignant hypertension

I3C

indole-3 carbinol

Ang

angiotensin

RAS

renin-angiotensin system
- Received April 12, 2001.
- Revision received July 9, 2001.
The American Society for Biochemistry and Molecular Biology, Inc.