The 129S1/SvlmJ mouse strain recapitulates severe hypertensive target organ damage under moderate angiotensin II–induced hypertension

Hypertension remains the leading cause of cerebral, cardiac, renal, and retinal vascular damage. However, genetic determinants underlying organ-specific vulnerability are poorly understood, and commonly used mouse models, notably C57BL/6J, often fail to recapitulate severe hypertensive complications seen in humans. This study compares the widely used C57BL/6J mouse strain with the genetically distinct 129S1/SvlmJ strain under hypertensive stress, aiming to identify a model that better reproduces hypertensive target organ damage. Moderate hypertension was induced in 129S1/SvlmJ and C57BL/6J mice using chronic infusion of angiotensin II (600 ng/kg/min). Despite comparable blood pressure elevations, only 129S1/SvlmJ mice developed severe organ damage, including cognitive impairment, pronounced blood-brain barrier disruption, retinal vasculopathy, cardiac hypertrophy, and podocyte lesions with albuminuria. In contrast, C57BL/6J mice exhibited markedly less organ injury under the experimental conditions tested. Transcriptomic analysis of cerebral microvessels identified distinct inflammatory and immune-related signatures between strains, paralleling their vascular phenotypes. These immune profiles appear as hallmarks of strain-specific susceptibility rather than as direct protective or deleterious mechanisms. This study demonstrates that genetic background critically shapes hypertensive complications, identifying the 129S1/SvlmJ strain as a relevant and translational model of hypertensive target organ damage. Beyond reproducing key features of severe hypertension, this model provides a framework to investigate the pathways linking genetic susceptibility, vascular injury, and end-organ damage.