title: Vascular dysfunction precedes hypertension associated with a blood pressure locus on rat chromosome 12.
abstract: We previously isolated a 6.1-Mb region of SS/Mcwi (Dahl salt-sensitive) rat chromosome 12 (13.4-19.5 Mb) that significantly elevated blood pressure (BP) (Δ+34 mmHg, P < 0.001) compared with the SS-12(BN) consomic control. In the present study, we examined the role of vascular dysfunction and remodeling in hypertension risk associated with the 6.1-Mb (13.4-19.5 Mb) locus on rat chromosome 12 by reducing dietary salt, which lowered BP levels so that there were no substantial differences in BP between strains. Consequently, any observed differences in the vasculature were considered BP-independent. We also reduced the candidate region from 6.1 Mb with 133 genes to 2 Mb with 23 genes by congenic mapping. Both the 2 Mb and 6.1 Mb congenic intervals were associated with hypercontractility and decreased elasticity of resistance vasculature prior to elevations of BP, suggesting that the vascular remodeling and dysfunction likely contribute to the pathogenesis of hypertension in these congenic models. Of the 23 genes within the narrowed congenic interval, 12 were differentially expressed between the resistance vasculature of the 2 Mb congenic and SS-12(BN) consomic strains. Among these, Grifin was consistently upregulated 2.7 ± 0.6-fold (P < 0.05) and 2.0 ± 0.3-fold (P < 0.01), and Chst12 was consistently downregulated -2.8 ± 0.3-fold (P < 0.01) and -4.4 ± 0.4-fold (P < 0.00001) in the 2 Mb congenic compared with SS-12(BN) consomic under normotensive and hypertensive conditions, respectively. A syntenic region on human chromosome 7 has also been associated with BP regulation, suggesting that identification of the genetic mechanism(s) underlying cardiovascular phenotypes in this congenic strain will likely be translated to a better understanding of human hypertension.
authors.affiliation: Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, Wisconsin; Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin;
authors.forename: Sasha Z
authors.initials: SZ
authors.lastname: Prisco
authors.affiliation: Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin;
authors.forename: Jessica R C
authors.initials: JR
authors.lastname: Priestley
authors.affiliation: Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin;
authors.forename: Brian D
authors.initials: BD
authors.lastname: Weinberg
authors.affiliation: Biotechnology and Bioengineering Center, Medical College of Wisconsin, Milwaukee, Wisconsin; Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin;
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Prisco
authors.affiliation: Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, Wisconsin; Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin;
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Hoffman
authors.affiliation: Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, Wisconsin; Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin; Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin; and.
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Jacob
authors.affiliation: Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, Wisconsin; Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin;
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Flister
authors.affiliation: Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin;
authors.forename: Julian H
authors.initials: JH
authors.lastname: Lombard
authors.affiliation: Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, Wisconsin; Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin; Department of Dermatology, Medical College of Wisconsin, Milwaukee, Wisconsin jlazar@mcw.edu.
authors.forename: Jozef
authors.initials: J
authors.lastname: Lazar
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000235:genetics*; D002875:Chromosomes / Q000235:genetics; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism; D037161:Galectins / Q000235:genetics / Q000378:metabolism; D056426:Genetic Loci; D006973:Hypertension / Q000209:etiology / Q000235:genetics* / Q000503:physiopathology; D008638:Mesenteric Arteries / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D051381:Rats; D020303:Rats, Inbred Dahl; D017673:Sodium Chloride, Dietary; D015238:Sulfotransferases / Q000235:genetics / Q000378:metabolism; D014655:Vascular Resistance
chemical_list: D005136:Eye Proteins; C115484:GRIFIN protein, rat; D037161:Galectins; D017673:Sodium Chloride, Dietary; D015238:Sulfotransferases
keywords: Brown Norway; Dahl salt-sensitive; genetic; vessel