Hypertension (HTN) affects 1.5 billion people worldwide and is responsible for 8.5 million deaths each year. It affects large and small vessels in numerous organs, leading to microvascular damage in the brain, heart, kidneys, and retina. HTN complications result from elevated blood pressure (BP), individual susceptibility, and environmental factors. We investigated how individual susceptibility drives organ damage.

To identify mechanisms underlying susceptibility to hypertensive lesions.

Three-month-old mice from the 129S1/SvImJ (129/Sv) and C57BL/6 J strains were treated with angiotensin II (AngII; 600 ng/kg/min) or 0.9% saline for 4 weeks under identical housing and dietary conditions. We systematically evaluated markers of vascular injury in the brain, heart, kidneys, and eyes.

Both strains showed similar BP elevation under AngII infusion. However, only the hypertensive 129/Sv mice exhibited systemic HTN lesions: cerebral microbleeds, deficits in spatial learning and memory, blood-brain barrier (BBB) and blood-retinal hyperpermeability, left ventricular hypertrophy (LVH) evaluated with echocardiography, cardiac conduction abnormalities, albuminuria, and renal podocyte lesions (electron microscopy). We performed bulk-RNA seq of brain microvessels to identify pathways involved in brain HTN microvascular damage. In hypertensive 129/Sv mice, we observed down-regulation of specific inflammatory pathways (interferon type I and purinergic pathways) compared to hypertensive C57BL/6 J strain, potentially contributing to their vulnerability to HTN-induced damage. These findings support the concept of protective low-grade inflammation based on two key observations. 1) Hypertensive C57BL/6 J mice displayed increased activation of brain tissue-resident and perivascular macrophages (IBA1+ and CD206+) in comparison to hypertensive 129/Sv mice. 2) In hypertensive 129/Sv mice, induction of low-grade inflammation through intraperitoneal LPS injections (0.25 mg/kg/week) did not reduce BP but prevented LVH, decreased albuminuria, and lowered BBB permeability ( Fig. 1 ).

We developed a model to explore the mechanisms of HTN organ damage. Despite similar BP, only hypertensive 129/Sv mice developed severe microvascular lesions linked to blunted inflammation. Low-grade inflammation prevented damage without lowering BP, challenging the view of inflammation as purely harmful and pointing to protective immune pathways.