title: Heterozygous disruption of activin receptor-like kinase 1 is associated with increased arterial pressure in mice.
abstract: The activin receptor-like kinase 1 (ALK-1) is a type I cell-surface receptor for the transforming growth factor-β (TGF-β) family of proteins. Hypertension is related to TGF-β1, because increased TGF-β1 expression is correlated with an elevation in arterial pressure (AP) and TGF-β expression is upregulated by the renin-angiotensin-aldosterone system. The purpose of this study was to assess the role of ALK-1 in regulation of AP using Alk1 haploinsufficient mice (Alk1(+/-)). We observed that systolic and diastolic AP were significantly higher in Alk1(+/-) than in Alk1(+/+) mice, and all functional and structural cardiac parameters (echocardiography and electrocardiography) were similar in both groups. Alk1(+/-) mice showed alterations in the circadian rhythm of AP, with higher AP than Alk1(+/+) mice during most of the light period. Higher AP in Alk1(+/-) mice is not a result of a reduction in the NO-dependent vasodilator response or of overactivation of the peripheral renin-angiotensin system. However, intracerebroventricular administration of losartan had a hypotensive effect in Alk1(+/-) and not in Alk1(+/+) mice. Alk1(+/-) mice showed a greater hypotensive response to the β-adrenergic antagonist atenolol and higher concentrations of epinephrine and norepinephrine in plasma than Alk1(+/+) mice. The number of brain cholinergic neurons in the anterior basal forebrain was reduced in Alk1(+/-) mice. Thus, we concluded that the ALK-1 receptor is involved in the control of AP, and the high AP of Alk1(+/-) mice is explained mainly by the sympathetic overactivation shown by these animals, which is probably related to the decreased number of cholinergic neurons.
authors.affiliation: Departamento de Fisiología y Farmacología, Universidad de Salamanca, Salamanca 37007, Spain Unidad de Fisiopatología Renal y Cardiovascular, Instituto 'Reina Sofía' de Investigación Nefrológica, Salamanca 37007, Spain Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca 37007, Spain.
authors.forename: María
authors.initials: M
authors.lastname: González-Núñez
authors.affiliation: Departamento de Fisiología y Farmacología, Universidad de Salamanca, Salamanca 37007, Spain Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca 37007, Spain Instituto de Neurociencias de Castilla y León (INCYL), Salamanca 37008, Spain.
authors.forename: Adela S
authors.initials: AS
authors.lastname: Riolobos
authors.affiliation: Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca 37007, Spain Instituto de Neurociencias de Castilla y León (INCYL), Salamanca 37008, Spain.
authors.forename: Orlando
authors.initials: O
authors.lastname: Castellano
authors.affiliation: Departamento de Fisiología y Farmacología, Universidad de Salamanca, Salamanca 37007, Spain Unidad de Fisiopatología Renal y Cardiovascular, Instituto 'Reina Sofía' de Investigación Nefrológica, Salamanca 37007, Spain Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca 37007, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Fuentes-Calvo
authors.affiliation: Departamento de Fisiología y Farmacología, Universidad de Salamanca, Salamanca 37007, Spain.
authors.forename: María
authors.initials: M
authors.lastname: de los Ángeles Sevilla
authors.affiliation: Departamento de Fisiología y Farmacología, Universidad de Salamanca, Salamanca 37007, Spain Unidad de Fisiopatología Renal y Cardiovascular, Instituto 'Reina Sofía' de Investigación Nefrológica, Salamanca 37007, Spain Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca 37007, Spain.
authors.forename: Bárbara
authors.initials: B
authors.lastname: Oujo
authors.affiliation: Departamento de Fisiología y Farmacología, Universidad de Salamanca, Salamanca 37007, Spain Unidad de Fisiopatología Renal y Cardiovascular, Instituto 'Reina Sofía' de Investigación Nefrológica, Salamanca 37007, Spain Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca 37007, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Pericacho
authors.affiliation: Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca 37007, Spain Departamento de Cardiología, Hospital Universitario de Salamanca, Salamanca 37007, Spain.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Cruz-Gonzalez
authors.affiliation: Departamento de Fisiología y Farmacología, Universidad de Salamanca, Salamanca 37007, Spain Unidad de Fisiopatología Renal y Cardiovascular, Instituto 'Reina Sofía' de Investigación Nefrológica, Salamanca 37007, Spain Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca 37007, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Pérez-Barriocanal
authors.affiliation: Department of Molecular Cell Biology, Leiden University Medical Center, Leiden 2333 ZA, The Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: ten Dijke
authors.affiliation: Departamento de Fisiología y Farmacología, Universidad de Salamanca, Salamanca 37007, Spain Unidad de Fisiopatología Renal y Cardiovascular, Instituto 'Reina Sofía' de Investigación Nefrológica, Salamanca 37007, Spain Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca 37007, Spain jmlnovoa@usal.es.
authors.forename: Jose M
authors.initials: JM
authors.lastname: López-Novoa
mesh_terms: D030201:Activin Receptors, Type I / Q000172:deficiency* / Q000235:genetics; D030301:Activin Receptors, Type II; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D062186:Arterial Pressure / Q000187:drug effects / Q000235:genetics; D002490:Central Nervous System / Q000473:pathology / Q000503:physiopathology; D059329:Cholinergic Neurons / Q000473:pathology; D002940:Circadian Rhythm; D004305:Dose-Response Relationship, Drug; D020022:Genetic Predisposition to Disease; D057895:Haploinsufficiency; D006579:Heterozygote; D006973:Hypertension / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D012084:Renin-Angiotensin System / Q000187:drug effects; D013564:Sympathetic Nervous System / Q000201:enzymology / Q000503:physiopathology; D013997:Time Factors; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D030201:Activin Receptors, Type I; D030301:Activin Receptors, Type II; C498931:Acvrl1 protein, mouse
keywords: Activin receptor-like kinase 1; Angiotensin II; Animal model of human disease; Arterial pressure; Catecholamines; Intracerebroventricular injection; Nitric oxide; Sympathetic nervous system