SUMMARY Cerebral cavernous malformations (CCMs) are a cause of stroke and seizure for which no medical therapies exist. CCMs arise from loss of an adaptor complex that negatively regulates MEKK3-KLF2/4 signaling in brain endothelial cells, but upstream activators of this disease pathway remain unknown. Here, we identify endothelial TLR4 and the gut microbiome as critical stimulants of CCM formation. Activation of TLR4 by gram negative bacteria or lipopolysaccharide accelerates CCM formation, while genetic or pharmacologic blockade of TLR4 signaling prevents CCM formation in mice. Polymorphisms that increase expression of TLR4 or its co-receptor CD14 are associated with higher CCM lesion burden in humans. Germ-free mice are protected from CCM formation, and a single course of antibiotics permanently alters CCM susceptibility in mice. These studies identify unexpected roles for the microbiome and innate immune signaling in the pathogenesis of a cerebrovascular disease, as well as novel strategies for its treatment.

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Loss of Krit1 disables an angiogenic checkpoint by reducing TSP1 expression, thereby enabling cerebral cavernous malformation (CCM) formation. Lopez-Ramirez et al. propose that replacing TSP1 by TSP1 fragments or angiogenesis inhibitors may provide an approach to inhibit CCM development.

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Cerebral cavernous malformations (CCMs) are common neurovascular lesions caused by lossof-function mutations in one of three genes, including KRIT1 (CCM1), CCM2, and PDCD10 (CCM3), and generally regarded as an endothelial cell-autonomous disease. Here we reported that proliferative astrocytes played a critical role in CCM pathogenesis by serving as a major source of VEGF during CCM lesion formation. An increase in astrocyte VEGF synthesis is driven by endothelial nitric oxide (NO) generated as a consequence of KLF2 and KLF4-dependent elevation of eNOS in CCM endothelium. The increased brain endothelial production of NO stabilized HIF-1a in astrocytes, resulting in increased VEGF production and expression of a "hypoxic" program under normoxic conditions. We showed that the upregulation of cyclooxygenase-2 (COX-2), a direct HIF-1a target gene and a known component of the hypoxic program, contributed to the development of CCM lesions because the administration of a COX-2 inhibitor significantly prevented the progression of CCM lesions. Thus, non-cell-autonomous crosstalk between CCM endothelium and astrocytes propels vascular lesion development, and components of the hypoxic program represent potential therapeutic targets for CCMs.