Department of Cardiology, Thoraxcenter, University Medical Center Groningen, University of Groningen, Hanzeplein 1, PO Box 30001, Groningen 9700 RB, The Netherlands.
Cardiovasc Res. 2010 Jul 1;87(1):30-9. doi: 10.1093/cvr/cvq041. Epub 2010 Feb 5.
We intended to delineate the mechanisms of erythropoietin (EPO)-induced cardiac vascular endothelial growth factor (VEGF) production and to establish if VEGF is crucial for EPO-induced improvement of cardiac performance.
The effects of EPO on VEGF expression were studied in cultured cardiac cells and EPO-treated hearts. The role of VEGF in EPO-induced neovascularization was studied with two distinct VEGF-neutralizing antibodies or irrelevant control IgG in an aortic sprouting assay and in rats with heart failure (HF) after myocardial infarction (MI) treated with EPO. EPO-alfa (10 IU/mL) was used in vitro and darbepoetin alfa (40 microg/kg/3 weeks, starting 3 weeks after MI) in vivo. EPO stimulated VEGF mRNA expression through the signal transducers and activators of transcription-3 (STAT-3) pathway in neonatal rat cardiomyocytes, but not in endothelial cells or fibroblasts. Similarly, the direct effects of EPO on endothelial sprouting were modest and VEGF independent. In rats with HF, EPO increased VEGF protein expression predominantly in cardiomyocytes, associated with a 37% increase in capillary density and improved cardiac performance. Administration of VEGF-neutralizing antibodies abrogated the salutary effects of EPO on cardiac microvascularization and function. VEGF neutralization attenuated EPO-induced proliferation of myocardial endothelial cells and reduced myocardial incorporation of endothelial progenitor cells (EPCs) in rats with alkaline phosphatase-labelled bone marrow cells.
VEGF is crucial for EPO-induced improvement of cardiac function in HF. EPO fosters VEGF expression predominantly in cardiomyocytes, which in turn stimulates myocardial endothelial proliferation and incorporation of EPCs.
我们旨在描述促红细胞生成素（EPO）诱导心脏血管内皮生长因子（VEGF）产生的机制，并确定 VEGF 是否对 EPO 诱导的心脏功能改善至关重要。
我们在培养的心脏细胞和 EPO 处理的心脏中研究了 EPO 对 VEGF 表达的影响。我们使用两种不同的 VEGF 中和抗体或无关的对照 IgG 在主动脉发芽测定中和在心肌梗死后心力衰竭（HF）大鼠中研究了 VEGF 在 EPO 诱导的新生血管形成中的作用。体外使用 EPO-alfa（10 IU/mL），体内使用达贝泊汀 alfa（40 μg/kg/3 周，在 MI 后 3 周开始）。EPO 通过信号转导和转录激活物 3（STAT-3）途径刺激新生大鼠心肌细胞中的 VEGF mRNA 表达，但不刺激内皮细胞或成纤维细胞。同样，EPO 对内皮发芽的直接作用较小且不依赖于 VEGF。在 HF 大鼠中，EPO 增加了 VEGF 蛋白表达，主要在心肌细胞中，同时毛细血管密度增加了 37%，心脏功能得到改善。给予 VEGF 中和抗体可消除 EPO 对心脏微血管化和功能的有益作用。VEGF 中和作用减弱了 EPO 诱导的心肌内皮细胞增殖，并减少了碱性磷酸酶标记的骨髓细胞大鼠中内皮祖细胞（EPC）的心肌内掺入。
VEGF 对 EPO 诱导 HF 心脏功能改善至关重要。EPO 促进 VEGF 主要在心肌细胞中表达，进而刺激心肌内皮细胞增殖和 EPC 掺入。
