Background and Hypothesis Angiogenesis triggered by inflammation increases BBB permeability and facilitates macrophage transmigration. In the midbrain, we have discovered molecular alterations related to the blood-brain barrier (BBB), including endothelial cell changes associated with macrophage diapedesis, in neuroinflammatory schizophrenia and bipolar disorder, but changes in angiogenesis are yet to be reported. Hypothesis: We expected to discover molecular evidence of altered angiogenesis in the midbrain in individuals with schizophrenia and bipolar disorder compared to controls, with these changes more evident in “high” inflammation schizophrenia as compared to “low” inflammation. Study Design In a case-control post-mortem cohort including schizophrenia (n = 35), bipolar disorder (n = 35), and controls (n = 33), we measured mRNA (RT-PCR) and protein (multiplex immunoassays) and performed immunohistochemistry to determine levels and anatomical distribution of angiogenesis-related molecules in the ventral midbrain. Study Results We found large changes in angiogenesis factors in bipolar disorder high inflammatory subgroup (increased angiopoietin-2 and SERPINE1 mRNAs, but decreased angiopoietin-1, angiopoietin-2, and TEK receptor proteins). In schizophrenia high inflammatory subgroup, we found a robust increase in SERPINE1 mRNA and protein levels. However, we found no significant changes in angiopoietins in schizophrenia. We found that VEGFA mRNA level was increased in high inflammation schizophrenia, but only reached statistical significance compared to one low inflammatory subgroup. Conclusions Thus, angiogenesis signaling pathways appeared to be involved in the BBB alterations when inflammation is also present in the midbrain of schizophrenia and bipolar disorder, with increased levels of SERPINE1 in schizophrenia high inflammatory subgroup and with a putative suppression of angiopoietin signaling in bipolar disorder high inflammatory subgroup.

中文翻译：

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神经炎症相关精神分裂症和双相情感障碍中血管生成改变的分子证据表明中脑血脑屏障异常


背景和假设 炎症触发的血管生成增加了 BBB 通透性并促进了巨噬细胞迁移。在中脑中，我们发现了与血脑屏障 （BBB） 相关的分子改变，包括与巨噬细胞透析相关的内皮细胞变化，在神经炎症性精神分裂症和双相情感障碍中，但血管生成的变化尚未报道。假设：与对照组相比，我们预计会发现精神分裂症和双相情感障碍个体中脑血管生成改变的分子证据，与“低”炎症相比，这些变化在“高”炎症精神分裂症中更为明显。研究设计 在包括精神分裂症 （n = 35）、双相情感障碍 （n = 35） 和对照 （n = 33） 在内的病例对照尸检队列中，我们测量了 mRNA （RT-PCR） 和蛋白质 （多重免疫测定） 并进行免疫组化以确定腹侧中脑中血管生成相关分子的水平和解剖分布。研究结果我们发现双相情感障碍高炎症亚组（血管生成素-2 和 SERPINE1 mRNA 增加，但血管生成素-1、血管生成素-2 和 TEK 受体蛋白减少）。在精神分裂症高炎症亚组中，我们发现 SERPINE1 mRNA 和蛋白质水平强劲增加。然而，我们发现精神分裂症患者的血管生成素没有显着变化。我们发现 VEGFA mRNA 水平在高炎症精神分裂症中升高，但与一个低炎症亚组相比仅达到统计学意义。 结论 因此，当精神分裂症和双相情感障碍的中脑也存在炎症时，血管生成信号通路似乎参与了 BBB 改变，精神分裂症高炎症亚组中SERPINE1水平升高，双相情感障碍高炎症亚组中推定血管生成素信号抑制。