Heterozygous disruption of activin receptor-like kinase 1 is associated with increased arterial pressure in mice

• Published in: Disease models & mechanisms Vol. 8; no. 11; pp. 1427 - 1439
• Main Authors: González-Núñez, María, Riolobos, Adela S, Castellano, Orlando, Fuentes-Calvo, Isabel, de los Ángeles Sevilla, María, Oujo, Bárbara, Pericacho, Miguel, Cruz-Gonzalez, Ignacio, Pérez-Barriocanal, Fernando, ten Dijke, Peter, López-Novoa, Jose M
• Format: Journal Article
• Language: English
• Published: England The Company of Biologists Ltd 01.11.2015; The Company of Biologists
• Subjects: Activin receptor-like kinase 1; Activin Receptors, Type I - deficiency; Activin Receptors, Type I - genetics; Angiotensin II; Angiotensin II Type 1 Receptor Blockers - pharmacology; Angiotensin-Converting Enzyme Inhibitors - pharmacology; Animal model of human disease; Animals; Antihypertensive Agents - pharmacology; Arterial pressure; Arterial Pressure - drug effects; Arterial Pressure - genetics; Atherosclerosis; Calcification; Cardiac function; Catecholamines; Central Nervous System - pathology; Central Nervous System - physiopathology; Cholinergic Neurons - pathology; Circadian Rhythm; Dose-Response Relationship, Drug; Electrocardiography; Genetic Predisposition to Disease; Growth factors; Haploinsufficiency; Heart rate; Heterozygote; High density lipoprotein; Homeostasis; Hypertension - drug therapy; Hypertension - enzymology; Hypertension - genetics; Hypertension - pathology; Hypertension - physiopathology; Intracerebroventricular injection; Kinases; Ligands; Mice, Inbred C57BL; Mice, Knockout; Nervous system; Nitric oxide; Phenotype; Proteins; Pulmonary hypertension; Renin-Angiotensin System - drug effects; Sympathetic nervous system; Sympathetic Nervous System - enzymology; Sympathetic Nervous System - physiopathology; Time Factors; Vasoconstriction - drug effects; Vasoconstrictor Agents - pharmacology; Vasodilation - drug effects; Vasodilator Agents - pharmacology; Intracerebroventricular injection; Nitric oxide; Activin receptor-like kinase 1; Arterial pressure; Catecholamines; Angiotensin II; Sympathetic nervous system; Animal model of human disease
• ISSN: 1754-8403; 1754-8411; 1754-8411; 1754-8403
• DOI: 10.1242/dmm.019695

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.