Kim Won, Moon Sang-Ok, Sung Mi Jeong, Kim Sung Hoon, Lee Sik, So June-No, Park Sung Kwang
Department of Internal Medicine, Research Institute of Clinical Medicine, Chonbuk National University Medical School, 634-18, Keum-Am dong, Chonju, 560-180, Republic of Korea.
FASEB J. 2003 Oct;17(13):1937-9. doi: 10.1096/fj.02-1209fje. Epub 2003 Aug 1.
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 AM22-52, 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.
肾上腺髓质素（AM）是人类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，我们研究了其对激酶和血管生成过程的影响。在人脐静脉内皮细胞（HUVECs）中，AM通过不同的信号通路诱导Akt和丝裂原活化蛋白激酶（MAPK）/细胞外信号调节激酶1/2（ERK1/2）的酪氨酸磷酸化。AM还使粘着斑激酶磷酸化，磷脂酰肌醇3'-激酶抑制剂可抑制AM诱导的粘着斑激酶磷酸化。用高浓度的AM22-52（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可使HUVECs的DNA合成和迁移增加。AM诱导HUVECs形成管腔，其作用可被磷脂酰肌醇3'-激酶抑制剂或ERK1/2抑制剂预处理所抑制。AM在猪肺动脉内皮细胞中诱导芽生，并在小鼠基质胶栓试验中促进新血管形成。磷脂酰肌醇3'-激酶和ERK1/2抑制剂在体外抑制AM诱导的内皮芽生，在体内抑制血管生成。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。
