Vascular Adhesion Laboratory, BSRC Alexander Fleming, 34 Fleming Street, Vari, 166 72 Athens, Greece.
Nat Commun. 2013;4:2020. doi: 10.1038/ncomms3020.
Genetic ablation of endothelial focal adhesion kinase (FAK) can inhibit pathological angiogenesis, suggesting that loss of endothelial FAK is sufficient to reduce neovascularization. Here we show that reduced stromal FAK expression in FAK-heterozygous mice unexpectedly enhances both B16F0 and CMT19T tumour growth and angiogenesis. We further demonstrate that cell proliferation and microvessel sprouting, but not migration, are increased in serum-stimulated FAK-heterozygous endothelial cells. FAK-heterozygous endothelial cells display an imbalance in FAK phosphorylation at pY397 and pY861 without changes in Pyk2 or Erk1/2 activity. By contrast, serum-stimulated phosphorylation of Akt is enhanced in FAK-heterozygous endothelial cells and these cells are more sensitive to Akt inhibition. Additionally, low doses of a pharmacological FAK inhibitor, although too low to affect FAK autophosphorylation in vitro, can enhance angiogenesis ex vivo and tumour growth in vivo. Our results highlight a potential novel role for FAK as a nonlinear, dose-dependent regulator of angiogenesis where heterozygous levels of FAK enhance angiogenesis.
内皮细胞焦点黏附激酶（FAK）的遗传缺失可抑制病理性血管生成，这表明内皮细胞 FAK 的缺失足以减少新生血管形成。在此，我们发现 FAK 杂合子小鼠中基质 FAK 表达的减少出人意料地增强了 B16F0 和 CMT19T 肿瘤的生长和血管生成。我们进一步证明，在血清刺激的 FAK 杂合子内皮细胞中，细胞增殖和微血管发芽增加，但迁移没有增加。FAK 杂合子内皮细胞中 pY397 和 pY861 处 FAK 磷酸化的不平衡而 Pyk2 或 Erk1/2 活性没有改变。相比之下，血清刺激的 Akt 磷酸化在 FAK 杂合子内皮细胞中增强，这些细胞对 Akt 抑制更敏感。此外，低剂量的药理 FAK 抑制剂，尽管低到无法影响体外 FAK 自身磷酸化，但可以增强体外血管生成和体内肿瘤生长。我们的结果突出了 FAK 作为血管生成的非线性、剂量依赖性调节因子的潜在新作用，其中 FAK 的杂合水平增强了血管生成。
