FVIII function during vascular development and angiogenesis

Hemophilia A (HA) is a bleeding disorder caused by the reduced activity of coagulation factor VIII (FVIII). The main clinical manifestations are prolonged bleeding occurring spontaneously, or in response to trauma. To date, there is not a definitive cure, and the treatment consists of replacement therapy of recombinant FVIII. Interestingly, FVIII deficiency is also correlated to cartilage degeneration, bone remodeling, renal and cardiovascular diseases, and intracranial hemorrhages (ICHs). Spontaneous ICHs represent the most serious cause of death in HA patients and the cause of the development is still unknown. We previously demonstrated that HA endothelial cells (ECs) are impaired in functionality, compared to healthy ECs, both in vitro and in vivo, and that ECs transcriptome profile is highly influenced by FVIII. Thus, we demonstrated that FVIII regulates the expression of endothelial basement membrane and extracellular matrix genes highlighting its role in the maintenance of ECs function. Within this project we aim to investigate if any difference occurs also in brain microvasculature, at functional level, by analyzing the endothelial network in the brain of wild type and HA mice at different ages. Moreover, combining transcriptomic, proteomic, and 3D model approaches, we will assess the role of FVIII in the development of the vascular system and we will characterize the molecular mechanism induced by FVIII necessary for the maintenance of a correct EC homeostasis.