FVIII regulates the molecular profile of endothelial cells: functional impact on the blood barrier and macrophage behavior

Abstract

Hemophilia A is an inherited X-linked recessive bleeding disorder caused by deficient activity of blood coagulation factor VIII (FVIII). In addition to a high risk of pathological bleeding, hemophilia patients show associated diseases including osteopenia, altered inflammation and vascular fragility. 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 o activated endothelium and transendothelial migration. By regulating vascular permeability plus leukocyte adhesion and transendothelial migration, the present work highlights new biological functions for FVIII.

The Vascular Endothelium and Coagulation: Homeostasis, Disease, and Treatment, with a Focus on the Von Willebrand Factor and Factors VIII and V

“…FVIII has also been associated with decreased endothelial cell adhesion, which could lead to higher rates of cell migration in the context of angiogenic sprouting and changes in the expression profile of genes originating from endothelial cells associated with the functional pathways involved in neural tube morphogenesis, cellular adhesion/migration, and the immune response. FVIII has also been associated with enhanced in vitro vascular tubule network formation and increased vascular endothelial permeability, among other effects [ 185 ].…”

Prevalence of non-Alcoholic Fatty Liver Disease and Associated Factors in Patients with Moderate or Severe Hemophilia: A Multicenter-Based Study

“…Emerging evidence also shows that FVIII is involved in multiple biological systems, including bone, vascular, and immune systems. 34 A dysregulation of the inflammatory processes has been observed in FVIII deficiency. 35 In patients with NAFLD, inflammation can be observed over liver lobules, even in the portal system which is associated with more advanced disease.…”

Hemostasis and endothelial functionality: the double face of coagulation factors

“…Cadé M et al 19 HUVECs Permeability -Bhat V et al 20 FVIII-deficient mice Angiogenesis -Sun H et al 21 HA patients FMD and VTI -Manon-Jensen T et al 22 HA patients ECM production -…”

“…Specifically, FVIII has been shown to induce transcriptional and functional changes in EC leading to a decrease in in vitro adherence and increased permeability, with paxillin as main mediator of these changes. 19 An altered and uncontrolled joint vascular remodeling has also been shown in FVIII-deficient mice after induction of hemarthrosis, suggesting a non-physiological angiogenic mechanism which could be a contributing cause of prolonged and repetitive bleedings. 20 Indeed, hemophilia A (HA) patients show reduced flow-mediated dilation (FMD) and hyperemic velocity time integral (VTI) compared to healthy controls, 21 pointing to alterations of both macrovascular and microvascular endothelial functions for which no clear culprit has yet been identified; we could speculate that the absence of FVIII itself might induce these impairments.…”