Controlled hypertension, a transgenic toggle switch reveals differential mechanisms underlying vascular disease.
A novel inbred rat model with inducible hypertension has been generated using a renin transgene under the transcriptional control of the cytochrome P450, Cyp1a1 promoter. 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.
Kantachuvesiri
S
S
Molecular Physiology Laboratory, University of Edinburgh Medical School, Wilkie Building, Teviot Place, Edinburgh EH8 9AG, United Kingdom.
Fleming
S
S
Peters
J
J
Peters
B
B
Brooker
G
G
Lammie
A G
AG
McGrath
I
I
Kotelevtsev
Y
Y
Mullins
J J
JJ
D000450:Aldosterone / Q000097:blood; D000803:Angiotensin I / Q000097:blood; D000804:Angiotensin II / Q000097:blood; D000818:Animals; D030801:Animals, Genetically Modified; D000975:Antioxidants / Q000494:pharmacology; D001794:Blood Pressure; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004792:Enzyme Precursors / Q000378:metabolism; D006973:Hypertension / Q000209:etiology* / Q000378:metabolism*; D017403:In Situ Hybridization; D007211:Indoles / Q000494:pharmacology; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007700:Kinetics; D051379:Mice; D010375:Pedigree; D007703:Peptidyl-Dipeptidase A / Q000097:blood; D011233:Precipitin Tests; D011401:Promoter Regions, Genetic; D051381:Rats; D011919:Rats, Inbred Strains; D012083:Renin / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic; D019076:Transgenes
D000975:Antioxidants; D004792:Enzyme Precursors; D007211:Indoles; D000804:Angiotensin II; D000450:Aldosterone; D000803:Angiotensin I; C016517:indole-3-carbinol; D007703:Peptidyl-Dipeptidase A; D012083:Renin