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Introduction: Cerebral cavernous malformations (CCM) are hemorrhagic lesions causing stroke and epilepsy. They develop with loss of function of three known genes in endothelial cells (ECs). Mice heterozygous for Ccm 1, 2 or 3 genes develop CCMs stochastically during life (“chronic models”), especially when bred in a background predisposing to somatic mutations (p53 or Msh2 loss). CCM lesions can also be generated in the developing hindbrain and retinas by Cre-recombinase induced homozygous loss of Ccm 1, 2, or 3 genes in the immediate postnatal period (“acute models”). We hypothesized that the CCM lesions which develop in the various models reflect different phenotypic features of the human disease.Methods: Eight murine models of CCM were used in this study and defined as being chronic (Ccm1+/-Msh2-/-, Ccm3+/- and Ccm3+/-Trp53-/-) or acute (PdgfbiCreERT2 Ccm1fl/fl, PdgfbiCreERT2 Ccm3fl/fl and Cdh5CreERT2 Ccm1fl/fl). Volumetric lesion burden was assessed using micro-CT after adjusting for total brain volume. Other phenotypic markers were assessed including the prevalence of ECs with Rho-associated protein kinase (ROCK) activity, and quantitation of B and T cells infiltration and non-heme iron deposition in the CCM lesions.Results: The acute neonatal models showed higher adjusted volume lesion burden than the paired chronic model (p=0.013). CCM EC ROCK activity was similar in the acute and chronic models. Background brain EC ROCK activity in chronic models was higher than that in acute model (p=0.012). CCM lesions in chronic models (16 lesions/13 mice) had higher integrated iron intensity per lesion area compared to the acute lesions (12 lesions/9 mice) (p=0.03). Chronic lesions had a higher number of B cells (p=0.005), more T cells (p=0.04) per lesion area, and more combined lymphocytes (p=0.002) per lesion area compared to the acute model.Conclusion: The acute model harbored a significantly higher lesion burden making them suitable for studying lesion genesis mechanisms. The chronic model however is more suited to study the role of inflammation and iron deposition in CCM, hallmark features of clinically relevant CCM lesions in man.