Department of Geriatrics, the Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China.
Peptides. 2012 Jan;33(1):92-100. doi: 10.1016/j.peptides.2011.11.001. Epub 2011 Nov 7.
Ghrelin, an endogenous ligand of the growth hormone secretagogue receptor (GHSR), is thought to exert a protective effect on the cardiovascular system, specifically by promoting vascular endothelial cell function such as cell proliferation, migration, survival and angiogenesis. However, the effect of ghrelin on angiogenesis and the corresponding mechanisms have not yet been extensively studied in cardiac microvascular endothelial cells (CMECs) isolated from left ventricular myocardium of adult Sprague-Dawley (SD) rats. In our study, we found that ghrelin and GHSR are constitutively expressed in CMECs. Ghrelin significantly increases CMECs proliferation, migration, and in vitro angiogenesis. The ghrelin-induced angiogenic process was accompanied by phosphorylation of ERK and Akt. MEK inhibitor PD98059 abolished ghrelin-induced phosphorylation of ERK, but had no effect on Akt phosphorylation. PI3K inhibitor LY294002 abolished ghrelin-induced phosphorylation of Akt, but had no effect on ERK phosphorylation. Ghrelin-induced angiogenesis was partially blocked by treatment with PD98059 or LY294002. In addition, this angiogenic effect was almost completely inhibited by PD98059+LY294002. Pretreatment with GHSR1a blocker [D-Lys3]-GHRP-6 abolished ghrelin-induced phosphorylation of ERK, Akt and in vitro angiogenesis. In conclusion, this is the first demonstration that ghrelin stimulates CMECs angiogenesis through GHSR1a-mediated MEK/ERK and PI3K/Akt signal pathways, indicating that two pathways are required for full angiogenic activity of ghrelin. This study suggests that ghrelin may play an important role in myocardial angiogenesis.
生长激素促分泌素受体（GHSR）的内源性配体 ghrelin 被认为对心血管系统具有保护作用，特别是通过促进血管内皮细胞功能，如细胞增殖、迁移、存活和血管生成。然而，ghrelin 对血管生成的影响及其相应的机制在从成年 Sprague-Dawley（SD）大鼠左心室心肌分离的心脏微血管内皮细胞（CMECs）中尚未得到广泛研究。在我们的研究中，我们发现 ghrelin 和 GHSR 在 CMECs 中持续表达。ghrelin 显著增加 CMECs 的增殖、迁移和体外血管生成。ghrelin 诱导的血管生成过程伴随着 ERK 和 Akt 的磷酸化。MEK 抑制剂 PD98059 消除了 ghrelin 诱导的 ERK 磷酸化，但对 Akt 磷酸化没有影响。PI3K 抑制剂 LY294002 消除了 ghrelin 诱导的 Akt 磷酸化，但对 ERK 磷酸化没有影响。PD98059 或 LY294002 处理部分阻断了 ghrelin 诱导的血管生成。此外，这种血管生成效应几乎被 PD98059+LY294002 完全抑制。GHSR1a 阻断剂[D-Lys3]-GHRP-6 的预处理消除了 ghrelin 诱导的 ERK、Akt 磷酸化和体外血管生成。总之，这是首次证明 ghrelin 通过 GHSR1a 介导的 MEK/ERK 和 PI3K/Akt 信号通路刺激 CMECs 血管生成，表明两种途径是 ghrelin 完全血管生成活性所必需的。这项研究表明，ghrelin 可能在心肌血管生成中发挥重要作用。
