Activated protein C induces endothelial cell proliferation by mitogen-activated protein kinase activation in vitro and angiogenesis in vivo
Activated protein C induces endothelial cell proliferation by mitogen-activated protein kinase activation in vitro and angiogenesis in vivo
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DOI：
10.1161/01.res.0000133680.87668.fa
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发表时间：
2004-07-09
影响因子：
20.1
通讯作者：
Suda, T
中科院分区：
文献类型：
--
作者：
Uchiba, M;Okajima, K;Suda, T
活化蛋白C（APC）是一种天然抗凝剂，最近被证明在体外激活内皮细胞中的丝裂原活化蛋白激酶（MAPK）通路。由于MAPK通路与内皮细胞增殖有关，APC可能诱导内皮细胞增殖，从而引起血管生成。我们在本研究中研究了这种可能性。APC依赖于其丝氨酸蛋白酶活性激活MAPK通路，增加DNA合成，并诱导培养的人脐静脉内皮细胞增殖。抗内皮蛋白C受体（EPCR）的抗体抑制这些事件。MAPK通路的早期激活被蛋白酶激活受体-1抗体抑制，而MAPK通路的晚期和完全激活以及内皮细胞增殖均未被该抗体抑制。APC通过磷脂酰肌醇3-激酶依赖性磷酸化激活内皮型一氧化氮合酶（eNOS），随后激活蛋白激酶G，表明APC结合EPCR可能通过类似于VEGF的机制激活内皮MAPK通路。APC诱导的形态发生变化类似于内皮细胞的管状结构，而DIP-APC没有。当局部应用于小鼠角膜时，APC明显诱导野生型小鼠的血管生成，但不在eNOS敲除小鼠中。这些在体外由APC诱导的事件可能至少部分地解释在体内的血管生成活性。APC的血管生成活性可能有助于维持适当的微循环，除了其抗血栓形成活性。
Activated protein C (APC), a natural anticoagulant, has recently been demonstrated to activate the mitogen-activated protein kinase ( MAPK) pathway in endothelial cells in vitro. Because the MAPK pathway is implicated in endothelial cell proliferation, it is possible that APC induces endothelial cell proliferation, thereby causing angiogenesis. We examined this possibility in the present study. APC activated the MAPK pathway, increased DNA synthesis, and induced proliferation in cultured human umbilical vein endothelial cells dependent on its serine protease activity. Antibody against the endothelial protein C receptor ( EPCR) inhibited these events. Early activation of the MAPK pathway was inhibited by an antibody against protease-activated receptor-1, whereas neither late and complete activation of the MAPK pathway nor endothelial cell proliferation were inhibited by this antibody. APC activated endothelial nitric oxide synthase ( eNOS) via phosphatidylinositol 3-kinase-dependent phosphorylation, followed by activation of protein kinase G, suggesting that APC bound to EPCR might activate the endothelial MAPK pathway by a mechanism similar to that of VEGF. APC induced morphogenetic changes resembling tube-like structures of endothelial cells, whereas DIP-APC did not. When applied topically to the mouse cornea, APC clearly induced angiogenesis in wild-type mice, but not in eNOS knockout mice. These in vitro events induced by APC might at least partly explain the angiogenic activity in vivo. This angiogenic activity of APC might contribute to maintain proper microcirculation in addition to its antithrombotic activity.