Thrombospondin1 (TSP1) replacement prevents cerebral cavernous malformations

• Published in: The Journal of experimental medicine Vol. 214; no. 11; pp. 3331 - 3346
• Main Authors: Lopez-Ramirez, Miguel Alejandro, Fonseca, Gregory, Zeineddine, Hussein A, Girard, Romuald, Moore, Thomas, Pham, Angela, Cao, Ying, Shenkar, Robert, de Kreuk, Bart-Jan, Lagarrigue, Frederic, Lawler, Jack, Glass, Christopher K, Awad, Issam A, Ginsberg, Mark H
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 06-11-2017; The Rockefeller University Press
• Subjects: Angiogenesis; Angiogenesis inhibitors; Animals; Brain; CCM1 protein; Cells, Cultured; Computed tomography; Deactivation; Endothelial cells; Endothelial Cells - metabolism; Gene expression; Gene Expression Profiling - methods; Genetic Therapy - methods; HEK293 Cells; Hemangioma, Cavernous, Central Nervous System - genetics; Hemangioma, Cavernous, Central Nervous System - metabolism; Hemangioma, Cavernous, Central Nervous System - therapy; Histology; Humans; Inactivation; Inhibitors; KLF4 protein; KRIT1 Protein - genetics; KRIT1 Protein - metabolism; Krueppel-like factor; Kruppel-Like Factor 4; Kruppel-Like Transcription Factors - genetics; Kruppel-Like Transcription Factors - metabolism; Lesions; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Microvasculature; Mutation; Pathogenesis; RNA Interference; Signaling; Thrombospondin 1 - genetics; Thrombospondin 1 - metabolism; Tight junctions; Vascular endothelial growth factor
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.20171178

mutations are the most common cause of cerebral cavernous malformation (CCM). Acute
gene inactivation in mouse brain microvascular endothelial cells (BMECs) changes expression of multiple genes involved in vascular development. These changes include suppression of
, which encodes thrombospondin1 (TSP1) and has been ascribed to KLF2- and KLF4-mediated repression of
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 (
) 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
exacerbated CCM formation. Thus, loss of
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.