{
  "abstract": "Background and Aims. Hemophilia A (HA) is an X-linked bleeding disorder caused by factor VIII (FVIII) deficiency. Although spontaneous intracranial hemorrhage represents a severe complication, the underlying mechanisms remain unclear. Increasing evidence suggests that FVIII may contribute to endothelial cell homeostasis, raising the possibility that vascular defects in HA extend beyond impaired coagulation. This study aimed to characterize structural and functional alterations of the cerebral microvasculature in HA and to specifically investigate intrinsic defects of brain microvascular endothelial cells (BMECs), as well as their correction following FVIII gene therapy. Methods. Brains were collected from HA, wild-type (WT), and HA mice treated with a lentiviral vector expressing FVIII under the Stab2 promoter (LV-Stab2-FVIII-HA) at 8, 12, and 24 weeks of age. Microvascular density and vessel length were quantified by mCD31 immunofluorescence. Vascular permeability was assessed in vivo at 8 weeks using fluorescent dextrans (4 and 150 kDa) under basal conditions and after DMSO-induced stress, with extravasation measured at 5, 10, and 15 minutes. BMECs isolated from HA and WT mice were analyzed in vitro for proliferation and migration using wound healing assays. Results. HA mice showed significantly reduced microvascular density and shorter vessel length compared to WT at all time points, indicating persistent cerebrovascular impairment. FVIII gene therapy induced a robust and sustained improvement of the vascular phenotype at all analyzed time points, with both vessel density and length markedly increased compared to untreated HA mice. Although these parameters did not fully reach WT levels, the differences between HA-LV-FVIII and WT mice were no longer statistically significant, indicating a substantial functional rescue by gene therapy for FVIII. Baseline permeability did not differ between groups; however, DMSO-induced stress caused a marked increase in dextran extravasation in HA mice at all time points, while WT vessels remained stable. Importantly, HA-derived BMECs exhibited significantly reduced proliferative capacity and impaired migratory ability compared to WT-BMECs, demonstrating an intrinsic endothelial dysfunction consistent with the in vivo phenotype. Conclusions. HA is associated with both structural defects and increased stress susceptibility of the cerebral microvasculature. The impaired proliferation and migration of HA-BMECs indicate a cell-autonomous endothelial dysfunction that likely contributes to vascular fragility. Restoration of FVIII expression via gene therapy rescues vascular architecture, supporting a direct role of FVIII in maintaining BMEC function and cerebrovascular integrity beyond its role in coagulation.",
  "abstract_shown": true,
  "affiliations": [],
  "article_type": null,
  "arxiv": null,
  "author_total": 1,
  "authors": [
    {
      "name": "Giorgia Venturin"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/58wtwgjzwwnh8.bib",
  "cited_by": 0,
  "doi": null,
  "fulltext_url": "https://www.btvb.org/btvb/article/view/783",
  "id": "58wtwgjzwwnh8",
  "issns": [
    "2785-5309"
  ],
  "landing_url": "https://www.btvb.org/btvb/article/view/783",
  "language": "en",
  "licence": "CC-BY-NC",
  "licence_label": "CC BY-NC",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by-nc/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "lcc",
      "RC666-701"
    ]
  ],
  "openalex": null,
  "pdf_url": null,
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-26",
  "publisher": "PAGEPress Publications",
  "ris": "https://research.draconitic.com/paper/58wtwgjzwwnh8.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T13:47:31Z",
      "native_id": "7fd09f76a2114bb3b00e388af92f30c4",
      "source": "doaj",
      "url": "https://www.btvb.org/btvb/article/view/783"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "lcc:RC666-701",
      "subfield": "cardiovascular"
    }
  ],
  "title": "CO081 | RESTORATION OF CEREBRAL MICROVASCULAR STRUCTURE AND FUNCTION IN HEMOPHILIA A MICE THROUGH FVIII GENE THERAPY",
  "title_text": "CO081 | RESTORATION OF CEREBRAL MICROVASCULAR STRUCTURE AND FUNCTION IN HEMOPHILIA A MICE THROUGH FVIII GENE THERAPY",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T13:47:31Z",
  "url": "https://research.draconitic.com/paper/58wtwgjzwwnh8",
  "venue": "Bleeding, Thrombosis and Vascular Biology",
  "versions": []
}