Abstract
BackgroundThe angiotensin II receptor subtype 2 (AT2 receptor) is ubiquitously and highly expressed in early postnatal life. However, its role in postnatal cardiac development remained unclear.Methodology/Principal FindingsHearts from 1, 7, 14 and 56 days old wild-type (WT) and AT2 receptor-deficient (KO) mice were extracted for histomorphometrical analysis as well as analysis of cardiac signaling and gene expression. Furthermore, heart and body weights of examined animals were recorded and echocardiographic analysis of cardiac function as well as telemetric blood pressure measurements were performed. Moreover, gene expression, sarcomere shortening and calcium transients were examined in ventricular cardiomyocytes isolated from both genotypes. KO mice exhibited an accelerated body weight gain and a reduced heart to body weight ratio as compared to WT mice in the postnatal period. However, in adult KO mice the heart to body weight ratio was significantly increased most likely due to elevated systemic blood pressure. At postnatal day 7 ventricular capillarization index and the density of α-smooth muscle cell actin-positive blood vessels were higher in KO mice as compared to WT mice but normalized during adolescence. Echocardiographic assessment of cardiac systolic function at postnatal day 7 revealed decreased contractility of KO hearts in response to beta-adrenergic stimulation. Moreover, cardiomyocytes from KO mice showed a decreased sarcomere shortening and an increased peak Ca2+ transient in response to isoprenaline when stimulated concomitantly with angiotensin II.ConclusionThe AT2 receptor affects postnatal cardiac growth possibly via reducing body weight gain and systemic blood pressure. Moreover, it moderately attenuates postnatal vascularization of the heart and modulates the beta adrenergic response of the neonatal heart. These AT2 receptor-mediated effects may be implicated in the physiological maturation process of the heart.
Highlights
Angiotensin II activates at least two heptahelical receptor subtypes, the AT1 and AT2 receptor, and is known to play a major role in the pathophysiology of cardiovascular and renal diseases
The AT2 receptor affects postnatal cardiac growth possibly via reducing body weight gain and systemic blood pressure. It moderately attenuates postnatal vascularization of the heart and modulates the beta adrenergic response of the neonatal heart. These AT2 receptor-mediated effects may be implicated in the physiological maturation process of the heart
The use of angiotensin receptor blockers (ARBs) during pregnancy is associated with an increased probability for cardiac and renal dysplasia in newborn infants, thereby indicating that AT1 receptor blockade and/or unopposed endogenous stimulation of the AT2 receptor, the predominant angiotensin II receptor subtype in the fetal and early postnatal organism, may negatively affect cardiac as well as renal maturation and growth [10,11]
Summary
Angiotensin II activates at least two heptahelical receptor subtypes, the AT1 and AT2 receptor, and is known to play a major role in the pathophysiology of cardiovascular and renal diseases. The use of ARBs during pregnancy is associated with an increased probability for cardiac and renal dysplasia in newborn infants, thereby indicating that AT1 receptor blockade and/or unopposed endogenous stimulation of the AT2 receptor, the predominant angiotensin II receptor subtype in the fetal and early postnatal organism, may negatively affect cardiac as well as renal maturation and growth [10,11]. In this regard, the role of the AT2 receptor in postnatal development of the heart is rather unclear and has not been examined in detail so far.
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