Department of Medicine, and.
Department of Pharmacology, University of California, San Diego, La Jolla, California, USA.
J Clin Invest. 2021 Jul 1;131(13). doi: 10.1172/JCI139570.
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.
脑内海绵状血管畸形（CCMs）是由 KRIT1（CCM1）、CCM2 和 PDCD10（CCM3）这 3 个基因中的 1 个功能丧失性突变引起的常见神经血管病变，通常被认为是一种血管内皮细胞自主性疾病。在这里，我们报道增殖性星形胶质细胞在 CCM 发病机制中起着关键作用，因为它们是 CCM 病变形成过程中 VEGF 的主要来源。CCM 内皮细胞中 KLF2 和 KLF4 依赖性 eNOS 升高导致内皮一氧化氮（NO）产生增加，从而驱动星形胶质细胞中 VEGF 合成的增加。增加的脑内皮细胞产生的 NO 稳定了星形胶质细胞中的 HIF-1α，导致在正常氧条件下 VEGF 的产生和表达增加，并出现“缺氧”程序。我们表明，环氧化酶-2（COX-2）的上调，作为 HIF-1α 的直接靶基因和缺氧程序的已知组成部分，促进了 CCM 病变的发展，因为 COX-2 抑制剂的给药显著阻止了 CCM 病变的进展。因此，CCM 内皮细胞和星形胶质细胞之间的非细胞自主性串扰推动了血管病变的发展，缺氧程序的组成部分代表了 CCM 的潜在治疗靶点。
