Hypertension uncouples SARS-CoV-2 viral burden from lung injury through dysregulated host responses

Hypertension is among the strongest risk factors for severe COVID-19, yet the mechanisms by which pre-existing vascular dysfunction reshapes host responses to SARS-CoV-2 remain incompletely defined. Here we establish a physiologically relevant, infection-permissive hypertensive golden Syrian hamster model using chronic nitric oxide synthase inhibition that induces sustained blood pressure elevation with concentric cardiac remodeling and preserved systolic function. Following SARS-CoV-2 challenge, hypertensive animals develop accelerated and exacerbated diffuse alveolar damage characterized by amplified vascular injury, thrombosis, hemorrhage, and inflammatory infiltration. This heightened pathology occurs despite equivalent pulmonary viral RNA levels and infectious titers compared to normotensive controls, demonstrating a dissociation between viral burden and disease severity. Mechanistically, hypertension amplifies early induction of TNF-α and IL-1β, selective endothelial activation, delayed type I and II interferon responses, and transient metabolic derangements including bicarbonate deficit and stress hyperglycemia. These findings position hypertension as a determinant of host-pathology uncoupled from viral replication and provide a scalable, infection-permissive platform to evaluate vascular and immunomodulatory interventions for COVID-19 and future respiratory viral threats.