Astrocytes propel neurovascular dysfunction during cerebral cavernous malformation lesion formation
Miguel Alejandro Lopez-Ramirez, … , Issam A. Awad, Mark H. Ginsberg
Miguel Alejandro Lopez-Ramirez, … , Issam A. Awad, Mark H. Ginsberg
Published May 27, 2021
Citation Information: J Clin Invest. 2021;131(13):e139570. https://doi.org/10.1172/JCI139570.
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Research Article Angiogenesis Cell biology

Astrocytes propel neurovascular dysfunction during cerebral cavernous malformation lesion formation

Abstract

Cerebral cavernous malformations (CCMs) are common neurovascular lesions caused by loss-of-function mutations in 1 of 3 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-1α 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-1α 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.

Authors

Miguel Alejandro Lopez-Ramirez, Catherine Chinhchu Lai, Shady Ibrahim Soliman, Preston Hale, Angela Pham, Esau J. Estrada, Sara McCurdy, Romuald Girard, Riya Verma, Thomas Moore, Rhonda Lightle, Nicholas Hobson, Robert Shenkar, Orit Poulsen, Gabriel G. Haddad, Richard Daneman, Brendan Gongol, Hao Sun, Frederic Lagarrigue, Issam A. Awad, Mark H. Ginsberg

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Figure 5

COX-2 inhibition prevents CCM lesions in Pdcd10BECKO mice.

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COX-2 inhibition prevents CCM lesions in Pdcd10BECKO mice. (A) Prominent...
(A) Prominent lesions are present in the cerebellum and cerebrum of P13 Pdcd10BECKO mice. Intragastric administration of 40 mg/kg celecoxib for 4 consecutive days at P6 to P9 suppressed lesion formation. Quantification of lesion volumes by micro-CT analysis from mice at P13 treated with celecoxib or vehicle (SEM, n = 7 mice in each group). (B) Hematoxylin and eosin (pink and purple) or GFAP (red) staining of cerebral (hippocampal area) and cerebellar sections from Pdcd10BECKO mice after treatment with celecoxib or vehicle (n = 3). (C) Prominent lesions are present in the cerebellum and cerebrum of P80 Pdcd10BECKO mice. Oral gavage administration of 40 mg/kg celecoxib for 15 consecutive days at P55 to P70 suppressed lesion formation. Quantification of lesion volumes by micro-CT analysis from mice at P80 treated with celecoxib or vehicle (SEM, n = 12 or 14 mice in each group). (D) Hematoxylin and eosin (pink and purple) or GFAP (red) staining of cerebral (hippocampal area) and cerebellar sections from Pdcd10BECKO mice after treatment with celecoxib or vehicle (n = 3). (E and F) Quantification of Vegfa (E) or Nos3 (F) mRNA levels in P80 Pdcd10BECKO spinal cords after treatment with celecoxib or vehicle from experiments in (C) (SEM, n = 7 or 9 mice in each group). Data are mean ± SEM. *P < 0.05, **P < 0.01, as determined by Student’s t test. Scale bars: 1 mm (H&E), 200 μm (GFAP) (B and D).