Delayed Cerebral Ischemia as Progressive Neurovascular Unit Failure: A Hypothesis-Generating Perspective
- 1College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
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.
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BibTeX
@article{loubani2026delayed,
title = {{Delayed Cerebral Ischemia as Progressive Neurovascular Unit Failure: A Hypothesis-Generating Perspective}},
author = {Kareem Loubani and Ayesha Deed and Zubia Hafeez and Maleeha Urooj Farhan and Thaabit Raziq and Zahra Shafeeq and Saniyah Shaikh and Olena Bolgova and Ahmed Yaqinuddin and Volodymyr Mavrych},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = nov,
doi = {10.3390/ijms272110048},
url = {https://www.mdpi.com/1422-0067/27/21/10048},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Delayed Cerebral Ischemia as Progressive Neurovascular Unit Failure: A Hypothesis-Generating Perspective
AU - Kareem Loubani
AU - Ayesha Deed
AU - Zubia Hafeez
AU - Maleeha Urooj Farhan
AU - Thaabit Raziq
AU - Zahra Shafeeq
AU - Saniyah Shaikh
AU - Olena Bolgova
AU - Ahmed Yaqinuddin
AU - Volodymyr Mavrych
PY - 2026
DA - 2026/11/09
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms272110048
UR - https://www.mdpi.com/1422-0067/27/21/10048
AB - 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.
SN - 1422-0067
ER -