Prolyl hydroxylase domain-2 silencing induced by hydrodynamic limb vein injection enhances vascular regeneration in critical limb ischemia mice through activation of multiple genes.
Prolyl hydroxylase domain-2 silencing induced by hydrodynamic limb vein injection enhances vascular regeneration in critical limb ischemia mice through activation of multiple genes.
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DOI：
10.2174/156652321503150329003735
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发表时间：
2015-05
影响因子：
3.6
通讯作者：
Shourong Wu;Jing Zhang;Can Huang;Huizhen Jia;Yunxia Wang;Zhiling Xu;Li Yang-;M. Miyagishi;Vivi Kasim
中科院分区：
文献类型：
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作者：
Shourong Wu;Jing Zhang;Can Huang;Huizhen Jia;Yunxia Wang;Zhiling Xu;Li Yang-;M. Miyagishi;Vivi Kasim
治疗性血管重建术被认为是治疗缺血性疾病最有潜力的策略。成熟血管的重建是一个涉及多种血管生成因素的复杂过程，是功能性血管重建的关键。人们试图通过输送载体或其他可积极调节血管生成的大分子来促进功能性血管重建；然而，这些治疗性血管生成因子的输送方法大多局限于直接肌肉注射。在本研究中，我们发现，与肌肉注射相比，肢体静脉注射针对PHD2的裸露短发夹状RNA表达载体(ShPHD2)不仅可以更有效地增加HIF依赖和非HIF依赖的血管生成因子的表达，而且可以更有效地增加参与各种内源性途径的组织保护因子。我们还发现，PHD2沉默增强了固有的内源性恢复机制，因为这些因子的表达水平仅因缺血条件而略有上调。HLV注射shPHD2可促进成熟的功能性血管的形成，从而更有效地促进缺血后肢的恢复。这些结果表明，hLV转导shPHD2可能成为一种有希望的治疗策略，通过增强固有的内源性途径来促进危重肢体缺血性疾病的血管再生。
Therapeutic revascularization had been considered as the most potential strategy for treating ischemic diseases. Reconstruction of mature blood vessels, which is the key for functional revascularization, is a complex process involving multiple angiogenesis factors. Attempts had been made to promote functional revascularization by delivering vectors or other macromolecules that could positively regulate angiogenesis; however, the delivery method of these therapeutic angiogenesis factors had been mostly limited to direct intramuscular injection. In this study, we showed that compared to intramuscular injection, the hydrodynamic limb vein (HLV) injection of naked short-hairpin RNA expression plasmid targeting PHD2 (shPHD2) into critical himblimb ischemia mice could increase not only the expressions of HIF-dependent and HIF-independent angiogenic factors, but also tissue protective factors involved in various endogenous pathways more efficiently. We also found that PHD2-silencing enhanced innate endogenous recovery mechanism, as the expression levels of these factors had been slightly upregulated merely by the ischemic condition. Finally, we showed that HLV injection of shPHD2 promoted the formation of mature and functional vessels, and thus, enhances the recovery of ischemic hindlimbs more efficiently. These results suggest that HLV delivery of shPHD2 might become a promising treatment strategy to promote vascular regeneration in critical limb ischemia disease via enhancing innate endogenous pathways.