Impact of AT2 Receptor Deficiency on Postnatal Cardiovascular Development

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.背景 血管紧张素II 2型受体（angiotensin II receptor subtype 2, AT2 receptor）在出生后早期广泛且高表达，但其在出生后心脏发育中的作用仍不明确。 方法与主要结果 本研究提取1、7、14及56日龄野生型（wild-type, WT）和AT2受体敲除（AT2 receptor-deficient, KO）小鼠的心脏，开展组织形态计量分析、心脏信号通路及基因表达检测。同时记录受试动物的心脏重量与体质量，进行心脏功能超声心动图评估与遥测血压测量。此外，对分离自两种基因型小鼠的心室肌细胞进行基因表达、肌节缩短及钙瞬变分析。 研究结果显示：出生后阶段，KO小鼠体质量增长速度快于WT小鼠，心脏/体质量比低于WT小鼠；但成年KO小鼠的心脏/体质量比显著升高，这可能与全身性血压升高相关。出生后第7日，KO小鼠的心室毛细血管化指数及α-平滑肌肌动蛋白阳性血管密度均高于WT小鼠，但在青春期后恢复至正常水平。出生后第7日的超声心动图心脏收缩功能评估显示，经β肾上腺素能刺激后，KO小鼠心脏的收缩能力下降。此外，在与血管紧张素II共同刺激时，KO小鼠心肌细胞对异丙肾上腺素的肌节缩短反应减弱，且钙瞬变峰值升高。 结论 AT2受体可通过降低体质量增长与全身性血压，影响出生后心脏生长。此外，该受体可适度抑制心脏出生后血管生成，并调节新生心脏的β肾上腺素能应答。上述AT2受体介导的效应可能参与心脏的生理成熟进程。