Nantes Université, CNRS, US2B, UMR 6286, 44000, Nantes, France.
Institut de Cancérologie de l'Ouest, "Tumor Heterogeneity and Precision Medicine" Laboratory, Blvd Jacques Monod, 44805, Saint-Herblain cedex, France.
Cell Mol Life Sci. 2022 Feb 21;79(3):145. doi: 10.1007/s00018-022-04178-5.
Hemophilia A is an inherited X-linked recessive bleeding disorder caused by deficient activity of blood coagulation factor VIII (FVIII). In addition, hemophilia patients show associated diseases including osteopenia, altered inflammation and vascular fragility which may represent the consequence of recurrent bleeding or may be related to the direct FVIII deficiency. Nowadays, recombinant FVIII is proposed to treat hemophilia patients with no circulating FVIII inhibitor. Initially described as a coenzyme to factor IXa for initiating thrombin generation, there is emerging evidence that FVIII is involved in multiple biological systems, including bone, vascular and immune systems. The present study investigated: (i) the functional activities of recombinant human FVIII (rFVIII) on endothelial cells, and (ii) the impact of rFVIII activities on the functional interactions of human monocytes and endothelial cells. We then investigated whether rFVIII had a direct effect on the adhesion of monocytes to the endothelium under physiological flow conditions. We observed that direct biological activities for rFVIII in endothelial cells were characterized by: (i) a decrease in endothelial cell adhesion to the underlying extracellular matrix; (ii) regulation of the transcriptomic and protein profiles of endothelial cells; (iii) an increase in the vascular tubes formed and vascular permeability in vitro; and (iv) an increase in monocyte adhesion activated endothelium and transendothelial migration. By regulating vascular permeability plus leukocyte adhesion and transendothelial migration, the present work highlights new biological functions for FVIII.
血友病 A 是一种遗传性 X 连锁隐性出血性疾病，由凝血因子 VIII (FVIII) 活性缺乏引起。此外，血友病患者还伴有骨质疏松症、炎症改变和血管脆弱等相关疾病，这些可能是反复出血的结果，也可能与 FVIII 直接缺乏有关。目前，重组 FVIII 被提议用于治疗无循环 FVIII 抑制剂的血友病患者。最初被描述为因子 IXa 启动凝血酶生成的辅酶，有新的证据表明 FVIII 参与多个生物学系统，包括骨骼、血管和免疫系统。本研究调查了：(i) 重组人 FVIII (rFVIII) 对内皮细胞的功能活性，和 (ii) rFVIII 活性对人单核细胞和内皮细胞功能相互作用的影响。然后，我们研究了 rFVIII 是否对生理流动条件下单核细胞与内皮细胞的粘附具有直接影响。我们观察到 rFVIII 在内皮细胞中的直接生物学活性表现为：(i) 内皮细胞对基底细胞外基质的粘附减少；(ii) 内皮细胞的转录组和蛋白质谱的调节；(iii) 体外血管管形成和血管通透性增加；和 (iv) 激活的内皮细胞上单核细胞粘附和跨内皮迁移增加。通过调节血管通透性加上白细胞粘附和跨内皮迁移，本工作强调了 FVIII 的新生物学功能。
