Liang Lihuan, Tam Christina W, Pozsgai Gabor, Siow Richard, Clark Natalie, Keeble Julie, Husmann Knut, Born Walter, Fischer Jan A, Poston Robin, Shah Ajay, Brain Susan D
Cardiovascular Division, King's College London, Franklin-Wilkins Building, Waterloo Campus, London SE1 9NH, UK.
Hypertension. 2009 Dec;54(6):1254-61. doi: 10.1161/HYPERTENSIONAHA.109.129783. Epub 2009 Oct 26.
The vasodilator and vascular regulatory peptide adrenomedullin (AM), a member of the calcitonin gene-related peptide family of peptides, is predicted to play a pivotal protective role in cardiovascular dysfunction. The principle AM (AM1) receptor is composed of a G protein-linked calcitonin receptor-like receptor and a receptor activity-modifying protein (receptor activity-modifying protein 2). There is little knowledge of the receptors via which AM acts in diseases. Using smooth muscle-targeted receptor activity-modifying protein 2 transgenic mice with increased vascular density of functional AM1 receptors, we demonstrate that receptor activity-modifying protein 2 transgenic mice are not protected against angiotensin II-induced hypertension or cardiac hypertrophy. However, vascular hypertrophy, together with vascular cell adhesion molecule 1 and monocyte chemotactic protein 1 expression, is significantly reduced in the aortic walls of transgenic mice, as determined by histological techniques. This indicates that the AM1 vascular smooth muscle receptor can mediate local protection in vivo. This is supported by proliferation studies in cultured smooth muscle cells. By comparison, levels of hypotension and inflammation in a shock model were similar to those in wild-type mice. Thus, a role of the AM1 receptor in the vasoactive component could not be detected, and evidence is provided to show that the hypotensive response to AM is subject to desensitization in vivo. The finding that the vascular smooth muscle AM1 receptor acts at a local level to protect against hypertension-induced vascular hypertrophy and inflammation provides evidence that targeting this receptor may be a beneficial therapeutic approach.
血管舒张和血管调节肽肾上腺髓质素（AM）是降钙素基因相关肽家族的成员，预计在心血管功能障碍中起关键的保护作用。主要的AM（AM1）受体由G蛋白偶联的降钙素受体样受体和受体活性修饰蛋白（受体活性修饰蛋白2）组成。对于AM在疾病中发挥作用的受体了解甚少。利用功能性AM1受体血管密度增加的平滑肌靶向受体活性修饰蛋白2转基因小鼠，我们证明受体活性修饰蛋白2转基因小鼠不能抵御血管紧张素II诱导的高血压或心脏肥大。然而，通过组织学技术测定，转基因小鼠主动脉壁中的血管肥大以及血管细胞粘附分子1和单核细胞趋化蛋白1的表达显著降低。这表明AM1血管平滑肌受体可在体内介导局部保护作用。这在培养的平滑肌细胞增殖研究中得到了支持。相比之下，休克模型中的低血压和炎症水平与野生型小鼠相似。因此，未检测到AM1受体在血管活性成分中的作用，并且提供了证据表明体内对AM的降压反应会发生脱敏。血管平滑肌AM1受体在局部发挥作用以预防高血压诱导的血管肥大和炎症这一发现提供了证据，表明靶向该受体可能是一种有益的治疗方法。
