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

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.