Thrombospondin1 (TSP1) replacement prevents cerebral cavernous malformations

Abstract

<i>KRIT1</i> mutations are the most common cause of cerebral cavernous malformation (CCM). Acute <i>Krit1</i> gene inactivation in mouse brain microvascular endothelial cells (BMECs) changes expression of multiple genes involved in vascular development. These changes include suppression of <i>Thbs1</i>, which encodes thrombospondin1 (TSP1) and has been ascribed to KLF2- and KLF4-mediated repression of <i>Thbs1</i> In vitro reconstitution of TSP1 with either full-length TSP1 or 3TSR, an anti-angiogenic TSP1 fragment, suppresses heightened vascular endothelial growth factor signaling and preserves BMEC tight junctions. Furthermore, administration of 3TSR prevents the development of lesions in a mouse model of CCM1 (<i>Krit1^ECKO</i> ) as judged by histology and quantitative micro-computed tomography. Conversely, reduced TSP1 expression contributes to the pathogenesis of CCM, because inactivation of one or two copies of <i>Thbs1</i> exacerbated CCM formation. Thus, loss of <i>Krit1</i> function disables an angiogenic checkpoint to enable CCM formation. These results suggest that 3TSR, or other angiogenesis inhibitors, can be repurposed for TSP1 replacement therapy for CCMs.