Tissue type plasminogen activator regulates myeloid-cell dependent neoangiogenesis during tissue regeneration
Tissue type plasminogen activator regulates myeloid-cell dependent neoangiogenesis during tissue regeneration
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DOI：
10.1182/blood-2009-08-236851
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发表时间：
2010-05-27
期刊：
影响因子：
20.3
通讯作者：
Hattori, Koichi
中科院分区：
文献类型：
--
作者：
Ohki, Makiko;Ohki, Yuichi;Hattori, Koichi
心脏、脑和四肢的缺血是世界范围内发病率和死亡率的主要原因。组织型纤溶酶原激活剂（tPA）治疗可溶解血栓，改善缺血性疾病的临床结局。但是tPA改善缺血组织再生的潜在机制还不清楚。骨髓（BM）衍生的髓样细胞促进组织再生过程中的血管生成。在这里，我们报告了tPA的丝氨酸蛋白酶抑制剂耐药形式通过激活细胞外蛋白酶基质金属蛋白酶-9和纤溶酶来扩大髓样细胞池并动员CD4（+）CD11b（+）促血管生成的髓样细胞，这一过程依赖于血管内皮生长因子-A（VEGF-A）和Kit配体信号传导。tPA促进CD11b（+）细胞进入缺血组织，并增加新血管生成相关基因（包括VEGF-A）的表达。值得注意的是，移植骨髓来源的tPA动员的CD11b（+）细胞和VEGFR-1（+）细胞，而不是载体动员的细胞或CD11b（-）细胞，加速新血管形成和缺血组织再生。在后肢缺血模型中抑制VEGF信号传导抑制tPA诱导的新血管形成。因此，tPA动员骨髓中的CD11b（+）细胞，并增加全身和局部（细胞）VEGF-A，这可以在缺血恢复期间局部促进血管生成。tPA可能是有用的，以诱导治疗性血管重建再生医学领域的不断增长。（血。2010; 115（21）：4302 - 4312）
Ischemia of the heart, brain, and limbs is a leading cause of morbidity and mortality worldwide. Treatment with tissue type plasminogen activator (tPA) can dissolve blood clots and can ameliorate the clinical outcome in ischemic diseases. But the underlying mechanism by which tPA improves ischemic tissue regeneration is not well understood. Bone marrow (BM)-derived myeloid cells facilitate angiogenesis during tissue regeneration. Here, we report that a serpin-resistant form of tPA by activating the extracellular proteases matrix metalloproteinase-9 and plasmin expands the myeloid cell pool and mobilizes CD4(+)CD11b(+) proangiogenic, myeloid cells, a process dependent on vascular endothelial growth factor-A (VEGF-A) and Kit ligand signaling. tPA improves the incorporation of CD11b(+) cells into ischemic tissues and increases expression of neoangiogenesis-related genes, including VEGF-A. Remarkably, transplantation of BM-derived tPA-mobilized CD11b(+) cells and VEGFR-1(+) cells, but not carrier-mobilized cells or CD11b(-) cells, accelerates neovascularization and ischemic tissue regeneration. Inhibition of VEGF signaling suppresses tPA-induced neovascularization in a model of hind limb ischemia. Thus, tPA mobilizes CD11b(+) cells from the BM and increases systemic and local (cellular) VEGF-A, which can locally promote angiogenesis during ischemic recovery. tPA might be useful to induce therapeutic revascularization in the growing field of regenerative medicine. (Blood. 2010; 115(21): 4302-4312)