Assistant Professor The University of Texas Health Science Center at Houston
Introduction: Introduction: Brain arteriovenous malformation (bAVM)-associated intracerebral hemorrhage (ICH) leads to severe disabilities or even death. Endothelial KRAS mutation (KRAS-EC) is commonly detected in human bAVM, and the sufficiency of KRAS-EC on bAVM genesis is established. The underlying mechanism by which KRAS-EC causes ICH is largely unknown. The presence of microglia/macrophages (M/M) surrounding ruptured bAVM suggests that M/M-associated focal inflammation is strongly associated with ICH. We hypothesize that interaction between KRAS-EC and M/M increases inflammation and drives bAVM destabilization, leading to spontaneous ICH.
Methods: Methods: We used our novel bAVM mouse model (KRAS-bAVM mice), established by overexpression of mutant KRAS in the endothelium using AAV-BR1-KRAS (G12V) on C57BL/6 or Cx3cr1-gfp;Ccr2-rfp mice. Brain clearing/immunofluorescence staining and intravital imaging visualized the dynamic of M/M. The role of M/M in bAVM/ICH was tested with minocycline and clodronate liposomes. Human bAVM nidus is used to show clinical relevance.
Results: Results: We observed an abundance of M/M surrounding ruptured and unruptured bAVM territory in KRAS-bAVM mice and resected human bAVM nidus. The time-lapsed intravital imaging showed that macrophages infiltrated into the parenchyma of bAVM territory over time. Depletion of macrophages with clodronate liposomes attenuated early microbleeding/ICH. Finally, treatment with minocycline attenuated M/M activation/infiltration in bAVM territory and prevented ICH occurrence/loss of BBB junction proteins in KRAS-bAVM mice.
Conclusion : Conclusions: This study demonstrates a novel mechanism by which the interaction with M/M and KRAS-EC promotes bAVM destabilization. Therefore, suppressing M/M-associated inflammation may lead to new pharmacological therapies for preventing spontaneous ICH.
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