Hypertension (HTN) affects 1.5 billion people worldwide and is responsible for 8.5 million deaths each year. HTN affects large and small vessels in numerous organs, leading to microvascular damage in the brain (strokes, dementia), kidneys (chronic kidney disease), eyes (retina), and heart damages (hypertrophic cardiomyopathy) and arterial stiffness.

The objective was to study the mechanisms of HTN-induced microvascular damage.

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

Both strains developed similar HTN levels induced by AngII. However, only the 129/Sv mice exhibited HTN lesions: deficits in spatial learning and memory (Morris Water Maze and Probe test), cerebral microbleeds, blood-brain barrier hyperpermeability (TMR dextran 3kDa tracer), astrocyte activation (GFAP immunostaining), renal podocyte lesions (electron microscopy) with albuminuria, blood-retinal barrier disruption, left ventricular hypertrophy (LVH) evaluated with echocardiography, cardiac conduction abnormalities (QRS duration). We performed RNA sequencing of brain microvessels to identify pathways involved in HTN microvascular damages. In 129/Sv mice treated with AngII, we observed down-regulation of specific inflammatory pathways compared to the C57BL/6J strain, potentially contributing to their vulnerability to HTN-induced damage. These results were supported by increased brain tissue-resident et perivascular macrophage activation (IBA1 and CD206 immunostaining), heart, and kidney (complement pathway) in C57BL/6J mice after AngII treatment compared to the hypertensive 129/Sv strain. We induced low-grade inflammation via intraperitoneal lipopolysaccharide (LPS) injections weekly (0.25mg/kg) in 129/Sv mice with AngII administration. The hypertensive 129/Sv mice with LPS had significantly lower albuminuria at day 7, a lower BBB permeability than the same hypertensive strain without LPS (Figure) and did not develop LVH.

We have developed a new and original approach to studying the determinants of HTN complications. These results suggest low-grade systemic inflammation could be involved in the resilience of C57BL6/J against hypertensive microvascular damage and offer promising perspectives for refining inflammation pathways in HTN.