{
  "abstract": "Despite decades of investigation, delayed cerebral ischemia (DCI) remains the principal cause of secondary neurological injury following aneurysmal subarachnoid hemorrhage (aSAH). Successive paradigms including angiographic vasospasm, early brain injury, neuroinflammation, blood–brain barrier disruption, cortical spreading depolarization, microvascular dysfunction, oxidative stress, and metabolic failure have each explained important aspects of disease biology. However, these mechanisms have largely evolved as parallel explanations rather than components of an integrated model, leaving the dissociation between vasospasm and DCI, delayed onset, interpatient heterogeneity, and limited efficacy of vasospasm-directed therapies incompletely explained. This perspective proposes, as a hypothesis, progressive neurovascular unit (NVU) failure as a conceptual framework for DCI after aSAH. We integrate experimental, translational, and clinical evidence spanning vascular biology, neuroimmunology, cerebrovascular physiology, electrophysiology, metabolism, biomarker research, and therapeutic trials to develop a hypothesis-generating framework. The established mechanisms of DCI may represent interacting manifestations of progressive disruption of coordinated signaling among endothelial, vascular smooth muscle, pericyte, astrocytic, microglial, and neuronal compartments of the neurovascular unit. Within this framework, early brain injury may initiate NVU dysfunction, which is amplified by interacting vascular, barrier, inflammatory, electrophysiological, and metabolic disturbances, culminating in neuronal metabolic failure and tissue injury. Vasospasm is therefore positioned as one contributor to this process rather than a sufficient explanation for DCI. This framework offers a possible basis for interpreting clinical heterogeneity and therapeutic discordance while generating testable predictions for multimodal biomarker development, biological phenotyping, and mechanism-informed therapeutic strategies. The framework does not introduce new mechanisms; rather, it proposes a testable distinction between compensated NVU dysfunction and NVU failure, frames compartment-specific non-additive interactions as an empirical question, and organizes biomarkers by the NVU compartment they reflect. These proposals remain to be validated.",
  "abstract_shown": true,
  "affiliations": [
    "College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 10,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Kareem Loubani",
      "orcid": "0009-0004-1230-6354"
    },
    {
      "affs": [
        0
      ],
      "name": "Ayesha Deed",
      "orcid": "0009-0000-3272-786X"
    },
    {
      "affs": [
        0
      ],
      "name": "Zubia Hafeez"
    },
    {
      "affs": [
        0
      ],
      "name": "Maleeha Urooj Farhan",
      "orcid": "0009-0006-6713-3395"
    },
    {
      "affs": [
        0
      ],
      "name": "Thaabit Raziq",
      "orcid": "0009-0000-8952-5644"
    },
    {
      "affs": [
        0
      ],
      "name": "Zahra Shafeeq"
    },
    {
      "affs": [
        0
      ],
      "name": "Saniyah Shaikh",
      "orcid": "0009-0008-3715-582X"
    },
    {
      "affs": [
        0
      ],
      "name": "Olena Bolgova",
      "orcid": "0009-0002-9496-9754"
    },
    {
      "affs": [
        0
      ],
      "name": "Ahmed Yaqinuddin",
      "orcid": "0000-0001-7536-910X"
    },
    {
      "affs": [
        0
      ],
      "name": "Volodymyr Mavrych",
      "orcid": "0009-0009-1159-4573"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/1zxbaan0130jr.bib",
  "cited_by": 0,
  "doi": "10.3390/ijms272110048",
  "fulltext_url": null,
  "id": "1zxbaan0130jr",
  "issns": [
    "1422-0067"
  ],
  "landing_url": "https://www.mdpi.com/1422-0067/27/21/10048",
  "language": null,
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [],
  "openalex": null,
  "pdf_url": null,
  "pmcid": null,
  "pmid": null,
  "published": "2026-11-09",
  "publisher": "MDPI AG",
  "ris": "https://research.draconitic.com/paper/1zxbaan0130jr.ris",
  "sources": [
    {
      "first_seen": "2026-11-10T00:21:27Z",
      "native_id": "10.3390/ijms272110048",
      "source": "crossref",
      "url": "https://www.mdpi.com/1422-0067/27/21/10048"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "issn:1422-0067",
      "subfield": "general"
    }
  ],
  "title": "Delayed Cerebral Ischemia as Progressive Neurovascular Unit Failure: A Hypothesis-Generating Perspective",
  "title_text": "Delayed Cerebral Ischemia as Progressive Neurovascular Unit Failure: A Hypothesis-Generating Perspective",
  "type": "peer-reviewed",
  "updated_at": "2026-11-10T00:21:27Z",
  "url": "https://research.draconitic.com/paper/1zxbaan0130jr",
  "venue": "International Journal of Molecular Sciences",
  "versions": []
}