Non cell-autonomous effect of astrocytes on cerebral cavernous malformations

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-1α 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-1α 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.

Abortive Intussusceptive Angiogenesis Causes Multi-Cavernous Vascular Malformations

“…The high penetrance and resemblance of the embryonic CVP malformation to multicavernous CCM suggest that it will be a useful phenotype for pharmacologic or morpholino-based analyses. That said, the CVP does lacks CNS accessory cells, such as astrocytes, (Lopez-Ramirez et al, 2021) that that promote CCM development. Indeed, we recently reported that propranolol blocks the embryonic CVP malformation by β1 adrenergic receptor antagonism (Li et al, 2021), a result that comports with the beneficial effects of propranolol in murine CCM models (Li et al, 2021;Oldenburg et al, 2021) and in anecdotal reports in humans (Lanfranconi et al, 2020;Reinhard et al, 2016).…”