A novel mouse model of hypertensive emergency with multiorgan microvascular disease implicating the VEGFA/sFlt-1 balance
BackgroundHypertensive emergency (HTEM) is defined by abrupt blood pressure elevation with acute multi-organ damage, yet the mechanisms predisposing only a subset of hypertensive individuals to HTEM remain unclear. Progress has been limited by the lack of a mouse model that faithfully replicates human disease. We aimed to identify determinants of susceptibility to hypertensive microvascular injury and characterize a murine model of HTEM. MethodsMale C57BL/6J (B6J) and 129S2/SvPasCrl (129Sv) mice were exposed to severe hypertension via angiotensin II infusion combined with a high-salt diet. We assessed survival, renal and retinal injury, cardiac function and electrophysiology, vascular permeability, circulating angiogenic factors, and glomerular transcriptional profiles using single-cell RNA sequencing. Bone marrow transplantation and recombinant human PlGF-2 treatment were used to investigate mechanisms driving endothelial injury. ResultsDespite comparable blood pressure, 129Sv mice, but not B6J, developed malignant hypertension with albuminuria, acute kidney injury, retinal hemorrhages, microvascular leakage, cardiac dysfunction, and arrhythmias. Hypertensive 129Sv mice exhibited markedly elevated circulating sFlt-1. PlGF-2 supplementation partially reversed albuminuria, preserved glomerular ultrastructure, and reduced retinal hemorrhages. Bone marrow transfers revealed contributions from both hematopoietic and non-hematopoietic 129Sv compartments to sFlt-1 overproduction and organ injury. Single-cell transcriptomics revealed profound repression of angiogenic, metabolic, and stress-response pathways in glomerular endothelial cells, a repression partially restored by PlGF-2. ConclusionsWe identify 129Sv mice as a robust model of HTEM, exhibiting multi-organ microvascular injury that closely mirrors the human condition. Our results reveal blood-pressure-independent susceptibility to organ damage and implicate dysregulated VEGFA/sFlt-1 signaling as a central driver of endothelial dysfunction, highlighting angiogenic imbalance as a potential therapeutic target.