Introduction Hypertensive emergency (HTEM) is a disease defined by an acute, severe increase of arterial blood pressure (BP) associated with evidence of injury in target organs of hypertension (HTN), manifesting as retinopathy, central nervous system involvement (stroke, encephalopathy), heart failure, or renal injury. It is considered a systemic microvascular disease with features of hyperpermeability and thrombotic microangiopathy. Kidney involvement manifests as acute kidney injury associated with high levels of albuminuria, which is thought to reflect abnormal glomerular endothelium permeability. Our current pathophysiological understanding of this disease is incomplete. It mainly relies on a scheme involving a vicious circle of the renin-angiotensin-aldosterone system (RAAS) activation, which is not always verified in patients. We hypothesize that additional factors define small vessel tolerance to elevated BP. Here, we propose a novel mouse model of HTEM characterized by heightened microvascular sensitivity to severe HTN. Methods C57BL6/J and 129s2 wild-type male mice developed HTN caused by subcutaneous angiotensin II (AngII) infusion and high-salt diet for 7 or 14 days. Blood pressure levels were measured using the tail-cuff method and confirmed with femoral artery catheter telemetry. Kidney injury was assessed using urine albumin ELISA, standard formalin-fixed paraffin-embedded histology, and transmission electron microscopy. Retinas were dissected to look for hemorrhagic spots. We evaluated heart disease using ultrasound/Doppler measurements and EKG monitoring and assessed vascular permeability using intravenous Evans blue injection. Plasma soluble fms-like tyrosine kinase-1 (sFlt-1) was measured using ELISA. Recombinant human placenta growth factor 2 (PlGF-2) was administered subcutaneously using osmotic minipumps. Results We demonstrate a stark difference in tolerance to severely elevated BP between the two mouse strains. While C57BL6/J mice have no observable injury after 2 weeks of HTN challenge, 129s2 mice exhibit a rapidly lethal phenotype highly reminiscent of human HTEM. We observed evidence of kidney injury with high levels of albuminuria and a consistent loss of glomerular endothelial fenestrations. These mice also present with retinal haemorrhages, cardiac arrhythmia, and decreased cardiac output. We demonstrate that this systemic disease is characterized by heightened microvascular permeability. Critically, the dramatic sensitivity to HTN of 129s2 mice compared to C57BL6/J counterparts occurred without any difference in telemetry-verified BP, highlighting that BP-independent factors strongly determine target organ damage. Given the diffuse microvascular injury reminiscent of preeclampsia, we compared sFlt_1 levels in both genetic background. Indeed, only hypertensive 129S2 mice displayed substantial elevation of circulating levels of sFlt-1 in 129s2 mice. Re-establishing a proangiogenic balance with PlGF-2 infusion prevented mortality, retinal haemorrhages and decreased albuminuria. Conclusion We describe the first mouse model of HTEM with systemic involvement recapitulating the human disease and demonstrate the critical role of the pro/antiangiogenic balance in determining small vessel tolerance to severe HTN. This model suggests close pathophysiological similarities between HTEM and preeclampsia and is the first description of pathological endogenous sFlt-1 involvement in a nonpregnant mouse model. Furthermore, the comparison of two commonly used inbred mouse strains uncovers a strong genetically-driven endothelial phenotype that may have wider implication in nephrology and cardiovascular pathophysiology.