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

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 as increased TGF-β1 expression correlates with an elevation in arterial pressure (AP) and TGF-β expression is up-regulated by the renin-angiotensin-aldosterone system. The purpose of this study has been to assess the role of ALK-1 in regulating AP using the ALK-1 haploinsufficient mice (ALK-1+/−). We observed that systolic and diastolic AP was significantly higher in ALK-1+/− than in ALK-1+/+ mice, and all functional and structural heart parameters (echocardiography and electrocardiography) were similar in both groups. ALK-1+/− mice showed alterations in AP circadian rhythm with higher AP than ALK-1+/+ mice during most of the light period. Higher AP in ALK-1+/− mice is not due to a reduced NO-dependent vasodilator response or to an overactivation of the peripheral renin-angiotensin system. However, intra-cerebroventricular administration of losartan had a hypotensive effect in ALK-1+/− and not in ALK-1+/+ mice. ALK-1+/− mice showed a higher hypotensive response to the β-adrenergic antagonist atenolol and greater concentrations of epinephrine and norepinephrine in plasma than ALK-1+/+ mice. The number of brain cholinergic neurons in anterior basal forebrain was reduced in ALK-1+/− mice. Thus, we concluded that ALK-1 receptor is involved in the control of AP, and high AP shown by ALK-1+/−mice is explained mainly by the sympathetic overactivation shown by these animals, probably related to the decreased number of cholinergic neurons.