Department of Biochemistry and Biomedical Engineering, Center for Research in Cardiovascular Medicine, University at Buffalo, New York, USA.
Am J Physiol Heart Circ Physiol. 2011 Dec;301(6):H2422-32. doi: 10.1152/ajpheart.00343.2011. Epub 2011 Sep 30.
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.
骨骼肌具有令人印象深刻的再生能力，这种能力与旁分泌产生许多具有心血管益处的营养因子有关。利用肌肉的这种体液能力，我们最近基于肌肉内给予 VEGF-A(165) 展示了一种治疗心力衰竭的心脏外治疗方案。这种远隔器官修复机制激活了从注射的腿筋中产生的许多营养因子，其中基质衍生因子-1 (SDF1) 明显动员了表达 CXCR4 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 GATA4 以及几种主要的营养因子，特别是 IGF1 和 VEGF。SDF1 阻断消除了 CXCR4(+) 和 c-kit(+)祖细胞向心肌的募集，但对造血祖细胞谱系的影响不大。心脏祖细胞的敲低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，注射 VEGF 的腿筋继续合成心脏保护因子，即使在存在 SDF1 阻断的情况下，也有助于适度的心肌组织活力和功能。这些发现因此揭示了两种通过肌肉内 VEGF 激活的不同但协同的心脏治疗机制。虽然 SDF1/CXCR4 轴激活了祖细胞级联反应及其对肌肉内心肌发生的营养支持，但 VEGF 放大了骨骼肌旁分泌级联反应，能够独立于 SDF1 直接促进心肌存活。鉴于基于使用骨髓动员剂的心脏修复的最近临床试验令人失望，拟议的双重治疗模式值得进一步研究。
