Non cell-autonomous effect of astrocytes on cerebral cavernous malformations
Lopez-Ramirez, M. A. A.; Soliman, S. I.; Hale, P.; Lai, C. C.; Pham, A.; Estrada, E. J.; McCurdy, S.; Girard, R.; Verma, R.; Moore, T.; Lightle, R.; Hobson, N.; Shenkar, R.; Poulsen, O.; Haddad, G. G.; Daneman, R.; Gongol, B.; Sun, H.; Lagarrigue, F.; Awad, I. A.; Ginsberg, M.
Show abstract
Cerebral cavernous malformations (CCMs) are common neurovascular lesions caused by loss-of-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 report that proliferative astrocytes play 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 stabilizes HIF-1 in astrocytes, resulting in increased VEGF production and expression of a "hypoxic" program under normoxic conditions. We show that the upregulation of cyclooxygenase-2 (COX-2), a direct HIF-1 target gene and a known component of the hypoxic program, contributes to the development of CCM lesions because the administration of a COX-2 inhibitor significantly prevents 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.
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