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-ß (TGF-ß) family of proteins. Hypertension is related to TGF-ß1, because increased TGF-ß1 expression is correlated with an elevation in arterial pressure (AP) and TGF-ß 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 ß-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.

Increased oxidative stress, the renin-angiotensin system, and sympathetic overactivation induce hypertension in kidney androgen-regulated protein transgenic mice.

Gender differences in the incidence and severity of hypertension have suggested the involvement of a sex-dependent mechanism. Transgenic (Tg) mice overexpressing kidney androgen-regulated protein (KAP) specifically in kidney showed hypertension associated with oxidative stress. Reactive oxygen species (ROS) are strongly implicated in the pathological signaling leading to hypertension in a framework that includes renin-angiotensin system (RAS) activation, increased sympathetic activity, and cardiac remodeling. In this report, we observed that plasma levels of angiotensin II and catecholamines were increased in KAP Tg mice, compared with wild-type animals. Systemic administration of Tempol, a membrane-permeative superoxide dismutase mimetic, reduced arterial pressure as well as urinary excretion of oxidative stress markers and reduced both angiotensin II and norepinephrine plasma levels in KAP Tg mice. Intracerebroventricular administration of Tempol also reduced arterial pressure in Tg mice. Moreover, administration of apocynin and DPI, inhibitors of NADPH oxidase, a major source of ROS, also reduced arterial pressure and both angiotensin II and norepinephrine plasma levels in Tg mice. Thus, we analyzed the involvement of the RAS and sympathetic nervous system in KAP Tg mouse hypertension. Both captopril and losartan reduced arterial blood pressure in Tg mice, as also occurred after ß-adrenergic blockade with atenolol. Also, intracerebroventricular losartan administration reduced arterial pressure in KAP Tg mice. Our data demonstrate that hypertension in male KAP Tg mice is based on increased oxidative stress, increased sympathetic activity, and RAS activation. Moreover, our results suggest a role for increased oxidative stress in the CNS as a major cause of hypertension in these animals.