Angiogenic role of adrenomedullin through activation of Akt, mitogen-activated protein kinase, and focal adhesion kinase in endothelial cells
Angiogenic role of adrenomedullin through activation of Akt, mitogen-activated protein kinase, and focal adhesion kinase in endothelial cells
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DOI：
10.1096/fj.02-1209fje
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发表时间：
2003-08-01
期刊：
影响因子：
4.8
通讯作者：
Park, SK
中科院分区：
文献类型：
--
作者：
Kim, W;Moon, SO;Park, SK
肾上腺髓质素 (AM) 是人嗜铬细胞瘤中的一种多功能肽。为了评估 AM 是否可能是一种血管生成因子，我们检查了它对激酶和血管生成过程的影响。 AM 通过在人脐静脉内皮细胞 (HUVEC) 中使用不同的信号传导途径，诱导 Akt 和丝裂原激活蛋白激酶 (MAPK)/细胞外信号调节激酶 1/2 (ERK1/2) 的酪氨酸磷酸化。 AM 还磷酸化粘着斑激酶，并且磷脂酰肌醇3'-激酶抑制剂抑制AM 诱导的粘着斑激酶磷酸化。用高浓度 AM(22-52)（一种假定的 AM 受体拮抗剂）预处理，可部分抑制 AM 诱导的 Akt、ERK1/2 和粘着斑激酶的磷酸化。 AM 和血管内皮生长因子导致 HUVEC 中 DNA 合成和迁移的增加。 AM诱导HUVECs管形成，其作用被磷脂酰肌醇3'-激酶抑制剂或ERK1/2抑制剂预处理所抑制。在小鼠基质胶塞试验中，AM 诱导猪肺动脉内皮细胞出芽并促进新血管形成。磷脂酰肌醇 3'-激酶和 ERK1/2 抑制剂可抑制 AM 诱导的体外内皮萌芽和体内血管生成。 AM 通过激活内皮细胞中的 Akt、MAPK 和粘着斑激酶发挥血管生成活性。
Adrenomedullin ( AM) is a multifunctional peptide in human pheochromocytoma. To evaluate whether AM could be an angiogenic factor, we examined its effect on kinases and angiogenic processes. AM induced tyrosine phosphorylation of Akt and mitogen-activated protein kinase ( MAPK)/extracellular signal-regulated kinase1/2 (ERK1/2) by using distinct signaling pathways in human umbilical vein endothelial cells (HUVECs). AM also phosphorylated focal adhesion kinase, and phosphatidylinositol 3'-kinase inhibitor inhibited AM-induced focal adhesion kinase phosphorylation. Pretreatment with high concentrations of AM(22-52), a putative AM receptor antagonist, partially suppressed AM-induced phosphorylation of Akt, ERK1/2, and focal adhesion kinase. AM and vascular endothelial growth factor produced increases in DNA synthesis and migration in HUVECs. AM induced tube formation in HUVECs, and its effect was inhibited by pretreatment with phosphatidylinositol 3'-kinase inhibitor or ERK1/2 inhibitor. AM induced sprouting in porcine pulmonary arterial endothelial cells and promoted neovessel formation in a mouse Matrigel plug assay. Inhibitors of phosphatidylinositol 3'- kinase and ERK1/2 inhibited AM-induced endothelial sprouting in vitro and angiogenesis in vivo. AM exerts angiogenic activity through activation of Akt, MAPK, and focal adhesion kinase in endothelial cells.