Division of Neonatology, Brigham and Women's Hospital, Harvard Medical School, Thorn 1019, 75 Francis Street, Boston, MA, USA.
Angiogenesis. 2012 Sep;15(3):457-68. doi: 10.1007/s10456-012-9274-0. Epub 2012 May 5.
Fatty acid binding protein 4 (FABP4) plays an important role in regulation of glucose and lipid homeostasis as well as inflammation through its actions in adipocytes and macrophages. FABP4 is also expressed in a subset of endothelial cells, but its role in this cell type is not known. We found that FABP4-deficient human umbilical vein endothelial cells (HUVECs) demonstrate a markedly increased susceptibility to apoptosis as well as decreased migration and capillary network formation. Aortic rings from FABP4(-/-) mice demonstrated decreased angiogenic sprouting, which was recovered by reconstitution of FABP4. FABP4 was strongly regulated by mTORC1 and inhibited by Rapamycin. FABP4 modulated activation of several important signaling pathways in HUVECs, including downregulation of P38, eNOS, and stem cell factor (SCF)/c-kit signaling. Of these, the SCF/c-kit pathway was found to have a major role in attenuated angiogenic activity of FABP4-deficient ECs as provision of exogenous SCF resulted in a significant recovery in cell proliferation, survival, morphogenesis, and aortic ring sprouting. These data unravel a novel pro-angiogenic role for endothelial cell-FABP4 and suggest that it could be exploited as a potential target for diseases associated with pathological angiogenesis.
脂肪酸结合蛋白 4（FABP4）在调节葡萄糖和脂质稳态以及炎症方面发挥着重要作用，其在脂肪细胞和巨噬细胞中的作用。FABP4 也在一部分内皮细胞中表达，但它在这种细胞类型中的作用尚不清楚。我们发现，缺乏 FABP4 的人脐静脉内皮细胞（HUVEC）表现出明显更高的凋亡易感性，以及迁移和毛细血管网络形成减少。FABP4（-/-）小鼠的主动脉环显示出血管生成芽生减少，而通过 FABP4 的再构成可以恢复。FABP4 受到 mTORC1 的强烈调节，并受到 Rapamycin 的抑制。FABP4 调节了 HUVECs 中几个重要信号通路的激活，包括 P38、eNOS 和干细胞因子（SCF）/c-kit 信号的下调。其中，SCF/c-kit 通路在 FABP4 缺乏的 ECs 中血管生成活性减弱中起着主要作用，因为提供外源性 SCF 导致细胞增殖、存活、形态发生和主动脉环芽生显著恢复。这些数据揭示了内皮细胞-FABP4 的新的促血管生成作用，并表明它可以作为与病理性血管生成相关疾病的潜在靶点。
