The Sequential Vulnerability Framework: A Systems Biology Model of State-Dependent Neurovascular Susceptibility

The Sequential Vulnerability Framework proposes that adaptive neurovascular regulation establishes a transient physiological operating state that independently influences biological susceptibility to subsequent physical perturbations. Rather than viewing susceptibility as a fixed tissue characteristic, the framework integrates established principles of neurovascular coupling, blood–labyrinth barrier physiology, endothelial mechanotransduction, oxidative homeostasis, and systems biology to hypothesize that coordinated regulatory processes generate an emergent operating state capable of modifying subsequent biological responses. The framework is intentionally independent of any specific exposure mechanism and is presented as a falsifiable conceptual model rather than an established physiological principle. It generates experimentally testable predictions regarding exposure-order dependence, finite recovery kinetics, coordinated biomarker profiles, and multimodal physiological reconstruction of operating state. Although motivated by unresolved questions surrounding reported Anomalous Health Incidents, the proposed model is applicable to broader questions of adaptive neurovascular regulation and state-dependent biological responsiveness. This manuscript presents the biological rationale, mechanistic synthesis, experimental predictions, proposed validation strategies, limitations, and conceptual implications of the Sequential Vulnerability Framework as a systems-level hypothesis for future investigation.