Shahriar Sanjid, Biswas Saptarshi, Zhao Kaitao, Akcan Uğur, Tuohy Mary Claire, Glendinning Michael D, Kurt Ali, Wayne Charlotte R, Prochilo Grace, Price Maxwell Z, Stuhlmann Heidi, Brekken Rolf A, Menon Vilas, Agalliu Dritan
Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA.
Wyss Institute for Biologically Inspired Engineering, Boston, MA, USA.
Nat Neurosci. 2024 Oct;27(10):1904-1917. doi: 10.1038/s41593-024-01746-9. Epub 2024 Sep 10.
Newly formed leaky vessels and blood-brain barrier (BBB) damage are present in demyelinating acute and chronic lesions in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). However, the endothelial cell subtypes and signaling pathways contributing to these leaky neovessels are unclear. Here, using single-cell transcriptional profiling and in vivo validation studies, we show that venous endothelial cells express neoangiogenesis gene signatures and show increased proliferation resulting in enlarged veins and higher venous coverage in acute and chronic EAE lesions in female adult mice. These changes correlate with the upregulation of vascular endothelial growth factor A (VEGF-A) signaling. We also confirmed increased expression of neoangiogenic markers in acute and chronic human MS lesions. Treatment with a VEGF-A blocking antibody diminishes the neoangiogenic transcriptomic signatures and vascular proliferation in female adult mice with EAE, but it does not restore BBB function or ameliorate EAE pathology. Our data demonstrate that venous endothelial cells contribute to neoangiogenesis in demyelinating neuroinflammatory conditions.
新形成的渗漏血管和血脑屏障（BBB）损伤存在于多发性硬化症（MS）和实验性自身免疫性脑脊髓炎（EAE）的急性和慢性脱髓鞘病变中。然而，导致这些渗漏性新血管形成的内皮细胞亚型和信号通路尚不清楚。在此，我们通过单细胞转录谱分析和体内验证研究表明，静脉内皮细胞表达新生血管生成基因特征，并显示出增殖增加，导致成年雌性小鼠急性和慢性EAE病变中的静脉扩张和静脉覆盖率更高。这些变化与血管内皮生长因子A（VEGF-A）信号通路的上调相关。我们还证实了急性和慢性人类MS病变中新生血管生成标志物的表达增加。用VEGF-A阻断抗体治疗可减少成年雌性EAE小鼠的新生血管生成转录组特征和血管增殖，但不能恢复BBB功能或改善EAE病理。我们的数据表明，静脉内皮细胞在脱髓鞘神经炎症性疾病中促成新生血管生成。
