Pleiotrophin induces nitric oxide dependent migration of endothelial progenitor cells
Pleiotrophin induces nitric oxide dependent migration of endothelial progenitor cells
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DOI：
10.1002/jcp.21313
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发表时间：
2008-05-01
影响因子：
5.6
通讯作者：
Springer, Matthew L.
中科院分区：
文献类型：
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作者：
Heiss, Christian;Wong, Maelene L.;Springer, Matthew L.
多效生长因子（PTN）在缺血条件下产生，并且已显示在体内诱导血管生成。我们研究了PTN是否对促血管生成的早期内皮祖细胞（EPCs）发挥趋化作用，EPCs是一群循环细胞，据报道参与并刺激血管生成。在transwell测定中测量从健康人（n = 5）的血液分离的EPC的趋化性。PTN在10-500 ng/ml引起EPCs和人脐静脉内皮细胞（HUVECs）的剂量依赖性趋化，但不引起缺乏PTN受体的人冠状动脉平滑肌细胞（CASMCs）和T98 G胶质母细胞瘤细胞的趋化。趋化性的程度与血管生成因子VEGF和SDF-1 α诱导的趋化性相当。对PTN的趋化性被NOS抑制剂L-NNA和L-NMMA、NO清除剂PTIO、磷酸肌醇-3激酶抑制剂渥曼青霉素和鸟苷酸环化酶抑制剂ODQ阻断，表明EPC趋化性依赖于这些途径。PTN诱导NOS依赖的NO产生的程度与VEGF相似，如NO指示剂TNF-2所示。PTN促进内皮祖细胞和内皮细胞增殖的程度与VEGF相似，但不诱导CASMC增殖。虽然L-NNA消除了PTN诱导的EPCs和HUVECs迁移，但它并不抑制PTN和VEGF增强的增殖，并且本身也引起增殖。这些数据表明，PTN可能通过增加血管生成部位的内皮细胞和早期EPCs的局部数量来介导其促血管生成作用。
Pleiotrophin (PTN) is produced under ischemic conditions and has been shown to induce angiogenesis in vivo. We studied whether or not PTN exerts chemotaxis of pro-angiogenic early endothelial progenitor cells (EPCs), a population of circulating cells that have been reported to participate in and stimulate angiogenesis. Chemotaxis of EPCs, isolated from blood of healthy humans (n = 5), was measured in transwell assays. PTN at 10-500 ng/ml elicited dose-dependent chemotaxis of both EPCs and human umbilical vein endothelial cells (HUVECs), but not of human coronary artery smooth muscle cells (CASMCs) and T98G glioblastoma cells that lack PTN receptors. The degree of chemotaxis was comparable to that induced by the angiogenic factors VEGF and SDF-1 alpha. Chemotaxis to PTN was blocked by the NOS inhibitors L-NNA and L-NMMA, the NO scavenger PTIO, the phosphoinositide-3 kinase inhibitor wortmannin, and the guanylyl cyclase inhibitor ODQ, suggesting dependence of EPC chemotaxis on these pathways. PTN induced NOS-dependent production of NO to a similar degree as did VEGF, as indicated by the NO indicator DAF-2. PTN increased proliferation in EPCs and HUVECs to a similar extent as VEGF, but did not induce proliferation of CASMCs. While L-NNA abolished PTN-induced migration in EPCs and HUVECs, it did not inhibit PTN- and VEGF-enhanced proliferation and also caused proliferation by itself. These data suggest that PTN may mediate its pro-angiogenic effects by increasing the local number of not only endothelial cells but also early EPCs at angiogenic sites.