Systemic preconditioning by a prolyl hydroxylase inhibitor promotes prevention of skin flap necrosis via HIF-1-induced bone marrow-derived cells.
Systemic preconditioning by a prolyl hydroxylase inhibitor promotes prevention of skin flap necrosis via HIF-1-induced bone marrow-derived cells.
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DOI：
10.1371/journal.pone.0042964
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Tamaki T
中科院分区：
文献类型：
--
作者：
Takaku M;Tomita S;Kurobe H;Kihira Y;Morimoto A;Higashida M;Ikeda Y;Ushiyama A;Hashimoto I;Nakanishi H;Tamaki T
局部皮瓣常因血供严重中断而出现皮瓣坏死。虽然动物研究表明，在缺血组织血管生成增强，这种现象的临床应用还没有明确的策略。缺氧诱导因子1（HIF-1）在缺血性血管反应中起关键作用，其表达由脯氨酰羟化酶抑制剂二甲基草酰甘氨酸（DMOG）诱导。我们评估了术前通过全身引入DMOG稳定HIF-1是否能提高皮瓣存活率。在手术前48小时用DMOG腹膜内处理背部具有缺血皮瓣的小鼠。在DMOG处理的小鼠中，缺血皮瓣的新生血管的存活面积显著更大。在DMOG处理的小鼠的缺血皮瓣中存在显著较少的凋亡细胞。有趣的是，在DMOG处理后48小时内观察到循环内皮祖细胞（EPC）和骨髓增殖祖细胞的显著增加。此外，与野生型小鼠相比，杂合HIF-1α缺陷小鼠表现出更小的存活皮瓣面积，更少的循环EPCs和更多的凋亡细胞，而DMOG预处理突变小鼠完全恢复了这些参数。最后，用杂合缺陷骨髓细胞重建野生型小鼠显著降低皮瓣存活率。我们证明了通过单一的全身DMOG治疗瞬时激活HIF信号通路不仅上调了抗凋亡通路，而且还增强了新血管形成，伴随着骨髓来源的祖细胞数量的增加。
Local skin flaps often present with flap necrosis caused by critical disruption of the blood supply. Although animal studies demonstrate enhanced angiogenesis in ischemic tissue, no strategy for clinical application of this phenomenon has yet been defined. Hypoxia-inducible factor 1 (HIF-1) plays a pivotal role in ischemic vascular responses, and its expression is induced by the prolyl hydroxylase inhibitor dimethyloxalylglycine (DMOG). We assessed whether preoperative stabilization of HIF-1 by systemic introduction of DMOG improves skin flap survival. Mice with ischemic skin flaps on the dorsum were treated intraperitoneally with DMOG 48 hr prior to surgery. The surviving area with neovascularization of the ischemic flaps was significantly greater in the DMOG-treated mice. Significantly fewer apoptotic cells were present in the ischemic flaps of DMOG-treated mice. Interestingly, marked increases in circulating endothelial progenitor cells (EPCs) and bone marrow proliferative progenitor cells were observed within 48 hr after DMOG treatment. Furthermore, heterozygous HIF-1α-deficient mice exhibited smaller surviving flap areas, fewer circulating EPCs, and larger numbers of apoptotic cells than did wild-type mice, while DMOG pretreatment of the mutant mice completely restored these parameters. Finally, reconstitution of wild-type mice with the heterozygous deficient bone marrow cells significantly decreased skin flap survival. We demonstrated that transient activation of the HIF signaling pathway by a single systemic DMOG treatment upregulates not only anti-apoptotic pathways but also enhances neovascularization with concomitant increase in the numbers of bone marrow-derived progenitor cells.
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影响因子：
5.2
作者：
Jones, Carla P.;Pitchford, Simon C.;Lloyd, Clare M.;Rankin, Sara M.
通讯作者：
Rankin, Sara M.
影响因子：
29.4
作者：
Cummins, Eoin P.;Seeballuck, Fergal;Taylor, Cormac T.
通讯作者：
Taylor, Cormac T.
影响因子：
56.9
作者：
Asahara, T;Murohara, T;Isner, JM
通讯作者：
Isner, JM
影响因子：
20.3
作者：
Tepper, OM;Capla, JM;Gurtner, GC
通讯作者：
Gurtner, GC
DOI：
10.1073/pnas.0911921106
发表时间：
2009-12-01
影响因子：
11.1
作者：
Rey, Sergio;Lee, KangAe;Semenza, Gregg L.
通讯作者：
Semenza, Gregg L.