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

• Main Authors: María González-Núñez, Adela S. Riolobos, Orlando Castellano, Isabel Fuentes-Calvo, María de los Ángeles Sevilla, Bárbara Oujo, Miguel Pericacho, Ignacio Cruz-Gonzalez, Fernando Pérez-Barriocanal, Peter ten Dijke, Jose M. López-Novoa
• Format: Article
• Language: English
• Published: The Company of Biologists 2015-11-01
• Series: Disease Models & Mechanisms
• Subjects: Activin receptor-like kinase 1; Animal model of human disease; Angiotensin II; Arterial pressure; Catecholamines; Intracerebroventricular injection; Nitric oxide; Sympathetic nervous system
• Online Access: http://dmm.biologists.org/content/8/11/1427
• ISSN: 1754-8411; 1754-8403

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.