Abstract Body: Background and Purpose: Brain arteriovenous malformation (bAVM) is an important risk factor for intracranial hemorrhage. There is no FDP approved drug available to bAVM patients. More than 95% of bAVMs are sporadic and about 5% are familial. Activated KRAS gene somatic mutations have been detected in endothelial cells (ECs) in sporadic bAVMs. Hereditary hemorrhagic telangiectasia (HHT) represents one of the familial forms. More than 80% of HHT patients have mutations in endoglin (ENG) or activin receptor-like kinase-1 (Alk1) gene. Transgene mediated Alk1overexpression in ECs reduced AVM severity in mice with Alk1 or Eng gene deletion. However, it is difficult to express Alk1 or correct KRAS expression in all ECs in patients. Hypothesis: Reduction of ECs with bAVM causative gene mutations alleviates bAVM severity. Methods: To test the effect of Alk1 mutant ECs, PdgfbiCreER;Alk1^f/f mice were treated with low (0.01 mg/25g of body weight) and high doses (1.25 mg/25g) of tamoxifen (TM). To test the effect of Eng mutant ECs, R26RCreER;Eng^f/f mice that have a Rosa promoter driving and TM-inducible WT cre expression globally, and PdgfbiCreER;Eng^f/f mice that have a Pdgfb promoter driving and TM-inducible icre (a codon mutant cre) expression in ECs were used. Due to the location of Eng in chromosome, an increase of TM dose cannot enhance Eng deletion. R26RCreER;Eng^f/f and PdgfbiCreER;Eng^f/f mice were treated with the same dose of TM (2.5 mg/g for 3 days) at the beginning of model induction. The brains were taken 8 weeks after AVM induction to study vessel density, abnormal vessels, mural cell coverage, and microhemorrhage. Results: Compared to the low TM dose treated, high TM dose treated PdgfbiCre;Alk1^f/f mice have a lower level of Alk1 protein in the brain and more Alk1^- ECs, which were associated with increased number of abnormal vessels in bAVM lesion. Compared to R26RCreER;Eng^f/f group, PdgfbiCreER;Eng^f/f mice have a lower level of Eng proteins and more Eng^- ECs, and more abnormal vessels, CD68⁺ microglia/macrophages and hemorrhage, less vascular pericyte and smooth muscle coverage in bAVM lesion. The number of Alk1^- or Eng^- ECs were positively correlated with bAVMs severity. Conclusion: We showed a correlation between the number of ECs with mutant bAVM causative genes and bAVM severity. Reduction of mutant ECs can alleviate bAVM severity and be used to develop new therapies for bAVMs.