Physiological function and gene expression of adremnomedullinfamily : adrenal medullary cells and isolated blood vessels

肾上腺髓质素家族的生理功能和基因表达：肾上腺髓质细胞和离体血管

• 批准号: 10218206
• 负责人: WADA Akihiko
• 金额: $ 36.99万
• 依托单位: Miyazaki Medical College
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research on Priority Areas
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-10218206/
• 关键词: Bioactive peptide; Receptor; Gene expression; Brain microvessel endothelial cell; Glia cell; Vascular smooth muscle cell; Pregnant uterus; Adrenomedullin; PAMP; CRLR; RAMP; Adrenal chromaffin cells; Microvessels; Choroid plexus; Oligodendrog

1) Analysis of adrenomedullin (AM) receptors, calcitonin gene-related peptide (CGRP) receptors and amylin receptors :AM, CGRP and amylin are structurally homologus and they have similar physiological functions. However, receptors for these peptides have not well characterized. We studied receptors for these peptides in oligodendroglia KG1C cells. KG1C cells express caltitonin receptor-likereceptor (CRLR), receptor-activity-mocdifing protein (RAMP)-1, -2 and -3. We foundthat-AM acted on AM receptors (CRLR+RAMP-2, CRLR+RAMP-3) and CGRP1 receptors (CRLR+RAMP-1), CGRP acted on CGRP1 receptors and CGRP2 receptors, and amylin acted of CGRP1 receptors.2) Synthesis and secretion of AM and its receptors in brain microvessels and glial cells :Brain micovessels secreted AM into the brain parenchyma and the luminal side of the vessels, and the level of AM secreted to the luminal side of the vessels was one order higher than that reported previously. AM secretion from the brain microvessels was not … More stimulated by thrombin, lipopolysaccalide or cytokines differently form the secretion by the endotheial cells of peripheral vessels. However, the AM secretion to the luminal side was stimulated by the soluble factors derived from astrocytes. Endothelial cells and pericytes of brain microvessels expressde CRLR and RAMP-2 and -3, and AM stimulated CAMP production in these cells. In addition, we found that AM activated blood-brain barrier function by regulating p-glycoprotein, pinocytosis and integrity of tight junction of microvessels.3) Maintenance of pregnancy by AM and AM receptors :CRLR and RAMP-1 and -2 were expressed in the pregnant rat uterus. Expression of AM increased at the site of uterus attached to the placenta but not at the site not attached to the placenta or in the chorion. Uterus strip where the placenta was attached did not contract spontaneously, but began to contract periodically by the addition AM receptor antagonist, AM(22-52). These results suggest that AM and AM preceptors are involved in the maintenance of pregnancy by inhibiting the contraction of the uterus.4) Mechanism of dilatation of iris sphincter muscle :AM acted on AM preceptors and CGRP1 receptors in an autocrine/paracrine manner, and dilated the iris sphincter muscle by increasing NO and cAMP level. Less

1)肾上腺髓质素(AM)受体、降钙素基因相关肽(CGRP)受体和胰淀素受体的分析：AM、CGRP和胰淀素在结构上是同源的，具有相似的生理功能。然而，这些多肽的受体还没有得到很好的表征。我们研究了这些多肽在少突胶质细胞KG1C中的受体。KG1C细胞表达降钙素受体样受体(CRLR)、受体活性调节蛋白(RAMP)-1、-2和-3。我们发现-AM作用于AM受体(CRLR+RAMP-2，CRLR+RAMP-3)和CGRP1受体(CRLR+RAMP-1)，CGRP作用于CGRP1受体，胰淀素作用于CGRP1受体。2)脑微血管和神经胶质细胞AM及其受体的合成和分泌：脑小血管分泌AM到脑实质和血管管腔侧，分泌到血管管腔侧的AM水平比以前报道的高一个数量级。脑微血管分泌的AM不是…更多的是受到凝血酶、脂多糖或细胞因子的刺激，以不同的方式形成外周血管内皮细胞的分泌。而由星形胶质细胞产生的可溶性因子可刺激AM向腔侧的分泌。脑微血管内皮细胞和周细胞表达CRLR、RAMP-2和RAMP-3，AM刺激这些细胞产生cAMP。此外，我们还发现AM通过调节P-糖蛋白、吞噬作用和微血管紧密连接的完整性来激活血脑屏障功能。3)AM和AM受体维持妊娠：CRLR和RAMP-1和RAMP-2在妊娠大鼠子宫中表达。AM在附着于胎盘的子宫部位表达增加，而不附着于胎盘的部位或绒毛膜表达增加。附着胎盘的子宫条不是自发收缩，而是被添加AM受体拮抗剂AM(22-52)周期性地收缩。这些结果提示AM和AM受体通过抑制子宫收缩而参与维持妊娠。4)虹膜括约肌扩张的机制：AM以自分泌/旁分泌方式作用于AM受体和CGRP1受体，通过增加NO和cAMP水平来扩张虹膜括约肌。较少

项目成果

Hideyuki Kobayashi et al.: "A novel isoform of proadrenomedullin N-terminal peptide in adrenal chromaffin cells."Japanese Journal of Pharmacology. 76(Supppl.I). 136P (1998)

Hideyuki Kobayashi 等人：“肾上腺嗜铬细胞中肾上腺髓质素原 N 末端肽的一种新型亚型。”日本药理学杂志。

Hideyuki Kobayashi et al.: "A novel isoform of proadrenomedullin N-terminal peptide in adrenal chromaffin cells." Japanese Journal of Pharmacology. 76(Suppl.I). 136 (1998)

Hideyuki Kobayashi 等人：“肾上腺嗜铬细胞中肾上腺髓质素原 N 端肽的一种新亚型。”

Hideyuki Kobayashi et al.: "Adrenomedullin receptors in rat cerebral microvessels."Molecular Brain Research. 81. 1-6 (2000)

Hideyuki Kobayashi 等人：“大鼠脑微血管中的肾上腺髓质素受体。”分子脑研究。

Yanagita T et al.: "Regulation of uterine contractility by adrenomedullin in pregnant rat uterus"The Japanese Journal of Pharmacology. 88 (Suppl I). 146 (2002)

Yanagita T等人：“妊娠大鼠子宫中肾上腺髓质素对子宫收缩力的调节”日本药理学杂志。

Kis B et al.: "Adrenomedullin, an autocrine mediator of blood-brain barrier function"Hypertens Res.. 26. S61-S70 (2002)

Kis B 等人：“肾上腺髓质素，血脑屏障功能的自分泌介质”Hypertens Res.. 26. S61-S70 (2002)