The loss of vasculature in Spinal Cord Injury (SCI) contributes to secondary injury, expanding the injury to unharmed spinal cord (SC) regions. Understanding these mechanisms is crucial for developing therapeutic interventions.
Comprehensive analysis of the temporospatial dynamics of vascular injury and regeneration following SCI.
Adult C57BL/6J mice were subjected to clip-compression SCI (Th 6/7, 5g, 60s, n = 20) or sham injury (laminectomy, n = 4), and sacrificed at 1, 3, 7, 14, and 28 days (d) post-injury following intracardial fluorescein isothiocyanate (FITC)-Lectin perfusion. Histological analysis (CD31, FITC-Lectin, Ki-67, IgG, TER-119) assessed vascular changes, permeability, and proliferation within the injury epicenter (region 0 (R0), ± 0,5 mm) and two adjacent SC regions (R1: ± 1 mm, R2: ± 2.5 mm).
Perfusion loss (FITC-Lectin+/CD31+), was most severe in R0 and R1 at d3 (p < 0.01). Significant vascular loss in R2 started at d3 (p = 0.043). Perfusion was restored at d28 in R0 and R1, and at d7 in R2. Vessel density (CD31+) returned to baseline quicker (R0: d3, R1 and R2: d14). Vascular proliferation (CD31+/Ki-67+) manifested across all regions at d3 (p < 0.01), and most notably in R2 (p < 0.01). Vascular permeability for IgG remained disrupted until d3 in R0 and R1 and until d14 in R2.
Vascular injury is most severe initially and spreads to the surrounding SC regions. Gradual vascular regeneration occurs early and up to a considerable distance from the injury epicenter, highlighting the potential of early therapeutic interventions targeted at vascular repair and regeneration.
© 2025 The Authors.

Atraumatic subarachnoid haemorrhage (SAH) is associated with high morbidity and mortality. Proposed mechanisms for red blood cell (RBC) clearance from the subarachnoid space (SAS) are erythrolysis, erythrophagocytosis or through efflux along cerebrospinal fluid (CSF) drainage routes. We aimed to elucidate the mechanisms of RBC clearance from the SAS to identify targetable efflux pathways.
Autologous fluorescently-labelled RBCs along with PEGylated 40 kDa near-infrared tracer (P40D800) were infused via the cisterna magna (i.c.m.) in female reporter mice for lymphatics or for resident phagocytes. Drainage pathways for RBCs to extracranial lymphatics were evaluated by in vivo and in situ near-infrared imaging and by immunofluorescent staining on decalcified cranial tissue or dural whole-mounts.
RBCs drained to the deep cervical lymph nodes 15 min post i.c.m. infusion, showing similar dynamics as P40D800 tracer. Postmortem in situ imaging and histology showed perineural accumulations of RBCs around the optic and olfactory nerves. Numerous RBCs cleared through the lymphatics of the cribriform plate, whilst histology showed no relevant fast RBC clearance through dorsal dural lymphatics or by tissue-resident macrophage-mediated phagocytosis.
This study provides evidence for rapid RBC drainage through the cribriform plate lymphatic vessels, whilst neither fast RBC clearance through dorsal dural lymphatics nor through spinal CSF efflux or phagocytosis was observed. Similar dynamics of P40D800 and RBCs imply open pathways for clearance that do not impose a barrier for RBCs. This finding suggests further evaluation of the cribriform plate lymphatic function and potential pharmacological targeting in models of SAH.
Swiss National Science Foundation (310030_189226), SwissHeart (FF191155).
Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.

Magnetic resonance imaging-guided focused ultrasound combined with microbubbles injected in the bloodstream (MRIgFUS) temporarily increases the permeability of the blood-brain barrier (BBB), which facilitates the entry of intravenously administered adeno-associated viruses (AAVs) from the blood to targeted brain areas. To date, the properties of the AAVs used for MRIgFUS delivery resulted in cell transduction limited to MRIgFUS-targeted sites. Considering future clinical applications, strategies are needed to deliver genes to multiple locations and large brain volumes while creating minimal BBB modulation. Here we combine MRIgFUS with a vector that has enhanced biodistribution following brain entry, AAV2-HBKO, to mediate broad gene delivery to targeted brain regions at levels with potential therapeutic relevance. Expression of a reporter gene was achieved in 13% and 21% of all neurons present in the striatum and thalamus, respectively, while targeting only 28% of the brain regions with MRIgFUS. Compared with AAV9, MRIgFUS-mediated delivery of AAV2-HBKO showed greater diffusion in the brain and a higher percentage of the neurons expressing the transgene. MRIgFUS AAV2-HBKO gene delivery to the brain has the potential to reach levels that are functionally and clinically relevant, and this even when using relatively low intravenous AAV dosages, compared with what is currently used in clinical trials.
© 2022 The Author(s).

Cavernomas are multi-lumen and blood-filled vascular malformations which form in the brain and the spinal cord. They lead to hemorrhage, epileptic seizures, neurological deficits, and paresthesia. An effective medical treatment is still lacking, and the available murine models for cavernomas have several limitations for preclinical studies. These include disease phenotypes that differ from human diseases, such as restriction of the lesions to the cerebellum, and absence of acute hemorrhage. Additional limitations of current murine models include rapid development of lesions, which are lethal before the first month of age. Here, we have characterized a murine model that recapitulates features of the human disease: lesions develop after weaning throughout the entire CNS, including the spinal cord, and undergo acute hemorrhage. This provides a preclinical model to develop new drugs for treatment of acute hemorrhage in the brain and spinal cord, as an unmet medical emergency for patients with cavernomas.
© 2022 The Author(s).

Blood vessel growth and remodelling are essential during embryonic development and disease pathogenesis. The diversity of endothelial cells (ECs) is transcriptionally evident and ECs undergo dynamic changes in gene expression during vessel growth and remodelling. Here, we investigated the role of the histone acetyltransferase HBO1 (KAT7), which is important for activating genes during development and for histone H3 lysine 14 acetylation (H3K14ac). Loss of HBO1 and H3K14ac impaired developmental sprouting angiogenesis and reduced pathological EC overgrowth in the retinal endothelium. Single-cell RNA sequencing of retinal ECs revealed an increased abundance of tip cells in Hbo1-deficient retinas, which led to EC overcrowding in the retinal sprouting front and prevented efficient tip cell migration. We found that H3K14ac was highly abundant in the endothelial genome in both intra- and intergenic regions, suggesting that HBO1 acts as a genome organiser that promotes efficient tip cell behaviour necessary for sprouting angiogenesis. This article has an associated 'The people behind the papers' interview.
© 2021. Published by The Company of Biologists Ltd.