Intramuscular VEGF activates an SDF1-dependent progenitor cell cascade and an SDF1-independent muscle paracrine cascade for cardiac repair.
Intramuscular VEGF activates an SDF1-dependent progenitor cell cascade and an SDF1-independent muscle paracrine cascade for cardiac repair.
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DOI：
10.1152/ajpheart.00343.2011
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发表时间：
2011-09
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通讯作者：
David C Zisa;A. Shabbir;M. Mastri;T. Taylor;I. Aleksic;M. Mcdaniel;Gen Suzuki;Techung Lee
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作者：
David C Zisa;A. Shabbir;M. Mastri;T. Taylor;I. Aleksic;M. Mcdaniel;Gen Suzuki;Techung Lee
骨骼肌具有令人印象深刻的损伤后再生能力，这种能力与旁分泌产生的许多具有心血管益处的营养因子相结合。利用肌肉的这种体液能力，我们最近展示了一种基于肌肉内递送VEGF-A（165）的心外治疗方案，用于修复衰竭的仓鼠心脏。这种远端器官修复机制激活了许多营养因子从注射的腿筋中产生，其中基质衍生因子-1（SDF 1）显著动员了表达CXCR 4的多谱系祖细胞及其向心脏的募集。动员的骨髓祖细胞表达心脏转录因子肌细胞增强因子2c和GATA 4以及几种主要的营养因子，最显著的是IGF 1和VEGF。SDF 1阻断可消除CXCR 4（+）和c-kit（+）祖细胞的心肌募集，对造血祖细胞谱系的影响不明显。敲除心脏祖细胞导致心肌营养因子的剥夺，导致心肌发生和血管生成受损。然而，VEGF注射的腿筋继续合成心脏保护因子，即使在SDF 1阻断的情况下也有助于适度的心肌组织活力和功能。因此，这些发现揭示了两个不同的，但协同作用的心脏治疗机制激活肌内VEGF。而SDF 1/CXCR 4轴激活祖细胞级联和其营养支持心肌肌内，VEGF放大骨骼肌旁分泌级联能够直接促进心肌存活的SDF 1独立。鉴于最近基于使用骨髓动员剂的心脏修复的临床试验令人失望，建议的双重治疗模式值得进一步研究。
The skeletal muscle is endowed with an impressive ability to regenerate after injury, and this ability is coupled to paracrine production of many trophic factors possessing cardiovascular benefits. Taking advantage of this humoral capacity of the muscle, we recently demonstrated an extracardiac therapeutic regimen based on intramuscular delivery of VEGF-A(165) for repair of the failing hamster heart. This distal organ repair mechanism activates production from the injected hamstring of many trophic factors, among which stromal-derived factor-1 (SDF1) prominently mobilized multi-lineage progenitor cells expressing CXCR4 and their recruitment to the heart. The mobilized bone marrow progenitor cells express the cardiac transcription factors myocyte enhancer factor 2c and GATA4 and several major trophic factors, most notably IGF1 and VEGF. SDF1 blockade abrogated myocardial recruitment of CXCR4(+) and c-kit(+) progenitor cells with an insignificant effect on the hematopoietic progenitor lineage. The knockdown of cardiac progenitor cells led to deprivation of myocardial trophic factors, resulting in compromised cardiomyogenesis and angiogenesis. However, the VEGF-injected hamstring continued to synthesize cardioprotective factors, contributing to moderate myocardial tissue viability and function even in the presence of SDF1 blockade. These findings thus uncover two distinct but synergistic cardiac therapeutic mechanisms activated by intramuscular VEGF. Whereas the SDF1/CXCR4 axis activates the progenitor cell cascade and its trophic support of cardiomyogenesis intramuscularly, VEGF amplifies the skeletal muscle paracrine cascade capable of directly promoting myocardial survival independent of SDF1. Given that recent clinical trials of cardiac repair based on the use of marrow-mobilizing agents have been disappointing, the proposed dual therapeutic modality warrants further investigation.