title: Genetic modifiers of hypertension in soluble guanylate cyclase α1-deficient mice.
abstract: Nitric oxide (NO) plays an essential role in regulating hypertension and blood flow by inducing relaxation of vascular smooth muscle. Male mice deficient in a NO receptor component, the α1 subunit of soluble guanylate cyclase (sGCα1), are prone to hypertension in some, but not all, mouse strains, suggesting that additional genetic factors contribute to the onset of hypertension. Using linkage analyses, we discovered a quantitative trait locus (QTL) on chromosome 1 that was linked to mean arterial pressure (MAP) in the context of sGCα1 deficiency. This region is syntenic with previously identified blood pressure-related QTLs in the human and rat genome and contains the genes coding for renin. Hypertension was associated with increased activity of the renin-angiotensin-aldosterone system (RAAS). Further, we found that RAAS inhibition normalized MAP and improved endothelium-dependent vasorelaxation in sGCα1-deficient mice. These data identify the RAAS as a blood pressure-modifying mechanism in a setting of impaired NO/cGMP signaling.
authors.affiliation: Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA. Ebuys@partners.org
authors.forename: Emmanuel S
authors.initials: ES
authors.lastname: Buys
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Raher
authors.forename: Andrew
authors.initials: A
authors.lastname: Kirby
authors.forename: Mohd
authors.initials: M
authors.lastname: Shahid
authors.forename: Shahid
authors.initials: S
authors.lastname: Mohd
authors.forename: David M
authors.initials: DM
authors.lastname: Baron
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Hayton
authors.forename: Laurel T
authors.initials: LT
authors.lastname: Tainsh
authors.forename: Patrick Y
authors.initials: PY
authors.lastname: Sips
authors.forename: Kristen M
authors.initials: KM
authors.lastname: Rauwerdink
authors.forename: Qingshang
authors.initials: Q
authors.lastname: Yan
authors.forename: Robert E T
authors.initials: RE
authors.lastname: Tainsh
authors.forename: Hannah R
authors.initials: HR
authors.lastname: Shakartzi
authors.forename: Christine
authors.initials: C
authors.lastname: Stevens
authors.forename: Kelly
authors.initials: K
authors.lastname: Decaluwé
authors.forename: Maria da Gloria
authors.initials: Mda G
authors.lastname: Rodrigues-Machado
authors.forename: Rajeev
authors.initials: R
authors.lastname: Malhotra
authors.forename: Johan
authors.initials: J
authors.lastname: Van de Voorde
authors.forename: Tong
authors.initials: T
authors.lastname: Wang
authors.forename: Peter
authors.initials: P
authors.lastname: Brouckaert
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Daly
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Bloch
mesh_terms: D000818:Animals; D006152:Cyclic GMP / Q000235:genetics / Q000378:metabolism; D004730:Endothelium, Vascular / Q000201:enzymology; D005260:Female; D008040:Genetic Linkage; D015894:Genome, Human; D006162:Guanylate Cyclase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D006973:Hypertension / Q000201:enzymology / Q000235:genetics*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D040641:Quantitative Trait Loci; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000378:metabolism; D012083:Renin / Q000235:genetics / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000235:genetics*; D015290:Second Messenger Systems / Q000235:genetics*; D000071756:Soluble Guanylyl Cyclase; D013045:Species Specificity; D014664:Vasodilation / Q000235:genetics*
chemical_list: D018160:Receptors, Cytoplasmic and Nuclear; D012083:Renin; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP