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bioRxiv · 10.1101/2025.03.24.641145

Strain Matters: The 129S1/SvlmJ Mouse Model Reveals the Genetic and Inflammatory Susceptibility to Hypertensive Complications

Orieux, A.·Boulestreau, R.·Bats, M.-L.·Michot, M.·Boyer, A.·Dinet, V.·Vaurs, J.·Dufourcq, P.·Peghaire, C.·DUPLAA, c.·Couffinhal, T.·Rubin, S.
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Abstract

BackgroundHypertension is a leading cause of microvascular injury, yet the genetic determinants of organ-specific vulnerability remain poorly understood. Yest, we need good mouse models to investigate the complication of hypertension. This study investigates the role of genetic background in shaping hypertensive complications by comparing two mouse strains with divergent inflammatory responses. MethodsThree-month-old 129S1/SvlmJ and C57BL/6J mice received 600 ng/kg/min of angiotensin II (AngII) or saline. We compared the consequences of ANG2-induced blood pressure elevation on kidney function, BBB intergrity and cardiac hypertropy. Blood pressure (BP) was assessed by telemetry. Vascular injury markers in the brain, heart, kidneys, and retinas were systematically evaluated. ResultsBoth strains developed similar moderate hypertension with AngII. Only 129S1/SvlmJ mice exhibited spatial learning and memory deficits, blood-brain barrier hyperpermeability, astrocyte activation, retinal artery damage, hypertrophic cardiomyopathy, and renal podocyte lesions with urinary albumin/creatinine ratio (UACR) after AngII treatment. Transcriptomic analysis of brain microvessels highlighted strain-specific differences in gene regulation, particularly in inflammatory pathways, which may explain the higher vulnerability of 129S1/SvlmJ mice to hypertensive organ damage. These findings were supported in vivo by increased resident and perivascular macrophage recruitment in the brain of C57BL6/J mice under AngII compared to the 129S1/SvlmJ strain. ConclusionOur findings highlight the critical role of genetic background in shaping hypertensive complications. The 129S1/SvlmJ strain serves as a valuable model for dissecting the molecular mechanisms of hypertensive organ damage, emphasizing neurovascular inflammation as a potential therapeutic target. Translational PerspectiveThis study highlights the 129/Sv mouse strain as a superior translational model compared to the widely used C57BL/6J strain, which, despite being a standard in cardiovascular research, fails to reliably reproduce severe hypertensive organ complications. The 129/Sv strain closely mimics human hypertensive damage, including cerebral small vessel disease, nephropathy, cardiomyopathy, and retinopathy. Transcriptomic analysis of cerebral microvessels identifies maladaptive inflammation as a critical mechanistic driver of susceptibility. These findings underline the clinical relevance of genetic predisposition, improving risk stratification and providing a robust preclinical platform to develop targeted anti-inflammatory therapies aimed at preventing hypertension-induced end-organ damage in patients.

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Orieux, A., Boulestreau, R., Bats, M.-L., Michot, M., Boyer, A., Dinet, V., Vaurs, J., Dufourcq, P., Peghaire, C., DUPLAA, c., Couffinhal, T., Rubin, S.. 2025-03-26. Strain Matters: The 129S1/SvlmJ Mouse Model Reveals the Genetic and Inflammatory Susceptibility to Hypertensive Complications. https://doi.org/10.1101/2025.03.24.641145

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