Research on mechanisms for vascular action of adrenomedullin

肾上腺髓质素是一种血管扩张肽，血管壁是肾上腺髓质素循环的主要来源。肾上腺髓质素的血管作用最初被认为完全是由于cAMP的产生增加，即非内皮依赖性的血管扩张。然而，我们发现内皮剥离显著降低了肾上腺髓质素对啮齿动物主动脉环的血管扩张作用。此外，肾上腺髓质素诱导的内皮依赖性血管松弛主要是通过激活PI3-K/Akt通路实现的。目前已证实，该通路参与抗细胞凋亡、保护组织以及激活内皮型一氧化氮合酶(ENOS)等多种重要作用。此外，我们还报道了肾上腺髓质素基因在低氧条件下表达上调。肾上腺髓质素减轻肾缺血/再灌流损伤。使用肾上腺髓质素基因敲除小鼠的研究表明，肾上腺髓质素在胚胎血管形成中起着重要作用。肾上腺髓质素转基因小鼠耐受缺血/再灌注肾损伤，肾上腺髓质素基因敲除小鼠耐受肾上腺髓质素基因敲除小鼠。这些发现提示内源性肾上腺髓质素可能作为一种组织生存因子发挥重要作用。

Adrenomedullin is a vasodilatory peptide and major source of circulating adrenomedullin is the vascular wall. The vascular action of adrenomedullin was at first considered to solely due elevated cAMP production, I. e., endothelium-independent vasodilation. However, we found that endothelial denudation substantially reduced the vasodilatory action of adrenomedullin in rodent aortic rings. Furthermore, this adrenomedullin-induced endothelium-dependent vasorelaxation is exerted mostly through activation of the phosphatydil inositol 3-kinase (PI3-K)/Akt pathway. It has been well established that this pathway is involved in various important actions such as anti-apoptosis and tissue protection as well as activation of endothelial nitric oxide synthase (eNOS).Furthermore, we have reported that expression of the adrenomedullin gene is upregulated by hypoxia. Adrenomedullin abrogates ischemia/reperfusion renal injury. Studies using adrenomedullin gene knockout mice revealed that adrenomedullin plays an important role in vascular formation in embryos. Adrenomedullin transgenic mice were resistant to ischemia/reperfusion renal injury and adrenomedullin knockout mice vice versa. These findings suggest that endogenous adrenomedullin may play an important role as a tissue survival factor.