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Heterozygous Disruption of Activin Receptor-Like Kinase 1 Is Associated with Increased Arterial Pressure in Mice Marıá González-Núñez1,2,3, Adela S

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Heterozygous Disruption of Activin Receptor-Like Kinase 1 Is Associated with Increased Arterial Pressure in Mice Marıá González-Núñez1,2,3, Adela S © 2015. Published by The Company of Biologists Ltd | Disease Models & Mechanisms (2015) 8, 1427-1439 doi:10.1242/dmm.019695 RESEARCH ARTICLE Heterozygous disruption of activin receptor-like kinase 1 is associated with increased arterial pressure in mice Marıá González-Núñez1,2,3, Adela S. Riolobos1,3,4, Orlando Castellano3,4, Isabel Fuentes-Calvo1,2,3, Marıá de los Ángeles Sevilla1,Bárbara Oujo1,2,3, Miguel Pericacho1,2,3, Ignacio Cruz-Gonzalez3,5, Fernando Pérez-Barriocanal1,2,3, Peter ten Dijke6 and Jose M. López-Novoa1,2,3,* ABSTRACT ALK-1 is highly expressed in endothelial cells, but also in many The activin receptor-like kinase 1 (ALK-1) is a type I cell-surface other cell types (Gonzalez-Nunez et al., 2013). ALK-1 participates β β receptor for the transforming growth factor-β (TGF-β) family of in the signaling of TGF- 1, TGF- 3, bone morphogenetic β β proteins. Hypertension is related to TGF-β1, because increased protein (BMP) 9 and BMP-10. TGF- 1 and TGF- 3 bind the TGF-β1 expression is correlated with an elevation in arterial pressure TGF receptor type II (Pardali and Ten Dijke, 2012). BMP-9 binds (AP) and TGF-β expression is upregulated by the renin-angiotensin- preferentially to activin receptor type IIB, whereas BMP-10 binds aldosterone system. The purpose of this study was to assess the role activin receptor type IIA, activin receptor type IIB or the BMP of ALK-1 in regulation of AP using Alk1 haploinsufficient mice (Alk1+/−). receptor type II with comparable affinity (Townson et al., 2012). β We observed that systolic and diastolic AP were significantly higher in The complex of TGF- or BMP and the corresponding type II Alk1+/− than in Alk1+/+ mice, and all functional and structural cardiac receptor recruits and phosphorylates ALK-1, which becomes parameters (echocardiography and electrocardiography) were similar activated. Activated ALK-1 in turn phosphorylates the in both groups. Alk1+/− mice showed alterations in the circadian rhythm transcription factors Smad1/5/8. Phosphorylated Smads form a of AP, with higher AP than Alk1+/+ mice during most of the light period. heteromeric complex with Smad4, and the complex translocates Higher AP in Alk1+/− mice is not a result of a reduction in the into the nucleus, where it participates in the activation or repression NO-dependent vasodilator response or of overactivation of the of the transcription of specific genes (Pardali and Ten Dijke, 2012). β peripheral renin-angiotensin system. However, intracerebroventricular Many of the TGF- superfamily members are involved in administration of losartan had a hypotensive effect in Alk1+/− and not in cardiovascular diseases. There are some relationships between − β Alk1+/+ mice. Alk1+/ mice showed a greater hypotensive response to hypertension and the ALK-1 ligand TGF- . Acute administration of β the β-adrenergic antagonist atenolol and higher concentrations of TGF- 1 induces vasodilatation and a reduction in arterial pressure β epinephrine and norepinephrine in plasma than Alk1+/+ mice. The (AP; Santibanez et al., 2007). However, increased TGF- 1 number of brain cholinergic neurons in the anterior basal forebrain was expression is associated with an increase in AP (Lavoie et al., reduced in Alk1+/− mice. Thus, we concluded that the ALK-1 receptor is 2005). Furthermore, angiotensin II (AngII) and aldosterone, major − TGFβ1 involved in the control of AP, and the high AP of Alk1+/ mice is regulators of AP, increase mRNA expression and trigger its explained mainly by the sympathetic overactivation shown by these transformation to the active form, and AngII also increases the animals, which is probably related to the decreased number of expression of TGF receptor type II mRNA (reviewed by Gordon β cholinergic neurons. and Blobe, 2008). In addition, the administration of TGF- neutralizing antibodies reduces AP in a rat model of hypertension KEY WORDS: Activin receptor-like kinase 1, Animal model of human (Lavoie et al., 2005). TGF-β1 also plays a major role in cardiac disease, Angiotensin II, Arterial pressure, Catecholamines, remodeling by inducing hypertrophy of cardiomyocytes and Intracerebroventricular injection, Nitric oxide, Sympathetic nervous activation of extracellular matrix production (Bujak and system Frangogiannis, 2007; Goumans et al., 2009). The role of TGF-β superfamily members in atherosclerosis is INTRODUCTION controversial, but most studies support an inhibitory role for TGF-β in Activin receptor-like kinase 1 (ALK-1) is one of the type I progression of atherosclerosis (Grainger, 2004). However, it has been membrane receptors for some of the members of the transforming reported that some BMPs promote progression of atherosclerotic growth factor-β (TGF-β) family of proteins (Hawinkels et al., 2013). lesions. Increased concentrations of BMP-2, BMP-4 and BMP-6 in these lesions are associated with vascular calcification (Grainger, 1Departamento de Fisiologıá y Farmacologıa,́ Universidad de Salamanca, 2007). Furthermore, the ALK-1 ligand BMP-9 has been reported to be Salamanca 37007, Spain. 2Unidad de Fisiopatologıá Renal y Cardiovascular, Instituto ‘Reina Sofıá’ de Investigación Nefrológica, Salamanca 37007, Spain. involved in the control of glucose metabolism (Chen et al., 2003) and 3Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca 37007, iron homeostasis (Truksa et al., 2006). Spain. 4Instituto de Neurociencias de Castilla y León (INCYL), Salamanca 37008, 5 Not only its ligands but also ALK-1 itself is directly implicated in Spain. Departamento de Cardiologıa,́ Hospital Universitario de Salamanca, ACVRL1 Salamanca 37007, Spain. 6Department of Molecular Cell Biology, Leiden University cardiovascular diseases. Mutations of , the gene for ALK-1, Medical Center, Leiden 2333 ZA, The Netherlands. are associated with the appearance of hereditary hemorrhagic telangiectasia type 2, a vascular dysplasia characterized by *Author for correspondence ( [email protected]) telangiectasias in the skin, nose bleeds and arteriovenous This is an Open Access article distributed under the terms of the Creative Commons Attribution malformations in several organs, mainly in the liver (Johnson License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. et al., 1996; Shovlin et al., 1997). In some families with hereditary hemorrhagic telangiectasia type 2 and pulmonary arterial Received 22 December 2014; Accepted 27 August 2015 hypertension, variants in the ACVRL1 gene have been reported. Disease Models & Mechanisms 1427 RESEARCH ARTICLE Disease Models & Mechanisms (2015) 8, 1427-1439 doi:10.1242/dmm.019695 BMP signaling (Yao et al., 2008). Finally, ALK-1 seems to be able TRANSLATIONAL IMPACT to regulate vascular (Garrido-Martin et al., 2013) and renal fibrosis (Munoz-Felix et al., 2014). Clinical issue An important role for ALK-1 in vascular homeostasis is thus Hypertension, a predominant risk factor for cardiovascular disease, has evident. The purpose of this study, therefore, was to assess the role β a complex etiology. Proteins in the transforming growth factor- family, of ALK-1 in regulation of AP, using a previously described mouse including TGF-β1, play a major role in the development of hypertension Alk1 Alk1+/− Alk1 and its complications. TGF-β1 expression is upregulated by the renin- model of haploinsufficiency ( ), because knockout angiotensin-aldosterone system, and this is correlated with an elevation mice are embryonic lethal (Oh et al., 2000). Our data provide the in arterial pressure (AP). Activin receptor-like kinase 1 (ALK-1) is a first demonstration of the involvement of the ALK-1 signaling known cell surface receptor for several members of this family of pathway in the control of AP. proteins; however, its possible involvement in hypertension has never been assessed. The purpose of this study was to assess the role of ALK- +/− RESULTS 1 in regulating AP. An Alk1 haploinsufficient mouse (Alk1 ) model and Alk1 its control (Alk1+/+) were used to address this question, because Alk1 Phenotypic characterization of heterozygous mice knockout mice are not viable. To analyze the expression of ALK-1, the mRNA and protein levels were measured in lung and kidneys from Alk1+/− and Results Alk1+/+ adult mice, because ALK-1 is mainly expressed in Arterial pressure, heart rate and locomotor activity were measured +/− vascularized tissues (Gonzalez-Nunez et al., 2013). Our results in Alk1 and control mice using radiotelemetry. Transthoracic show that ALK-1 protein (Fig. S1A) and mRNA content echocardiography and telemetric electrocardiogram were also +/− +/− (Fig. S1B) in Alk1 mice is about half of that found in lungs performed. Systolic and diastolic AP were significantly higher in Alk1 +/+ +/+ Alk1 than in Alk1 mice. All functional and structural heart parameters were and kidneys from littermates. These data corroborate that +/− similar in both groups, and electrocardiographic analysis revealed no Alk1 mice are haploinsufficient for Alk1. Furthermore, we also − apparent abnormalities in Alk1+/ mice. Renal function was also found to analyzed other important components of the ALK-1 signaling − be unchanged. Interestingly, Alk1+/ mice showed alterations in AP pathway, such as the receptors ALK-5 and Endoglin, and we circadian rhythm; during the morning (light) period, AP was higher in the observed that their levels were not different between Alk1+/− and haploinsufficient mice than in wild-type
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