Brain arteriovenous malformations (bAVMs) are aberrant connections between arteries and veins with no intervening capillaries. They generally form during development in the absence of any family history, and result in tangled vessels prone to rupture. bAVMs are thus a rare but significant cause of childhood brain hemorrhage. While many bAVM patients have somatic mutations in the gene for signaling factor KRAS, the mutations don’t account for all cases or fully explain the condition’s pathology. Li and colleagues therefore took an unbiased look at bAVM patient genomes and transcriptomes to find other genes and pathways involved. They performed whole-exome sequencing of 60 patients and their unaffected parents, as well as transcriptome analysis of both bulk tissue and single cells from bAVM lesions. De novo mutations discovered through the exome analysis and dysregulated RNAs found through the transcriptome analyses pointed to a role for endothelial-to-mesenchymal transition (EndMT) in bAVM pathology. Furthermore, the team showed KRAS mutations themselves also promoted EndMT in endothelial cells, and that the drug Lovastatin could prevent EndMT in bAVM patient cells. The work thus not only reveals EndMT as a feature of bAVM, but offers hints to a possible therapy.

Kawasaki disease (KD) is a systemic inflammatory condition particularly affecting blood vessels that can develop in children and has no known etiology. The severe vasculitis can cause coronary artery aneurysm (CAA), which may be fatal. Standard treatment for KD is intravenous infusion of immunoglobulin, which lowers the raised levels of inflammatory cytokines IL-1β and IL-18 characteristic of the condition. However, some patients are resistant to this treatment, and genetic variants associated with such resistance point to alterations in the inflammasomes—multiprotein complexes that regulate cytokine secretion. To understand more about the inflammasome-cytokine pathway in KD, Porrit and colleagues examined the inflamed aortas of KD model mice, finding that monocytes, macrophages and dendritic cells were the main sources of IL-1β in such vessels and that vascular smooth muscle cells (VSMCs) were the likely targets. KD VSMCs adopted a more migratory and more proliferative phenotype to those of control vessels, and blocking IL-1β signaling prevented this disease phenotype. It also prevented cardiovascular inflammation in the model mice, as did inflammasome inhibition. This work thus supports the development of inflammasome-targeted drugs for the treatment of KD, especially for immunoglobulin-resistant cases.

Endothelial-to-mesenchymal transition (EndMT) is a process in which the features of endothelial cells (ECs) are replaced with those of more migratory and invasive fibroblasts. EndMT is a normal part of organogenesis, such as during heart valve development, but is also a pathological process in some diseases including atherosclerosis, pulmonary hypertension and Kawasaki disease. While the transcription factor SLUG is known to drive EndMT, the full set of molecular players that promote or prevent the process is unknown. Now, using two separate models of EndMT in human ECs Liang and colleagues find the transcriptional regulator LARP7 is downregulated upon EndMT initiation, and that depletion of LARP7 in ECs is sufficient to induce fibroblast features. Chromatin immunoprecipitation experiments further revealed that LARP7 associates with the SLUG gene promoter in ECs where it recruited the transcriptional repressor TRIM28. Indeed, deletion of TRIM28 could also induce EndMT. Lastly, in mouse embryos whose endocardium lacked LARP7, TRIM28 or both, heart and aortic valves were thickened with evidence of overgrowth that was not seen in control animals. This more complete understanding of the control of EndMT should offer insights into diseases where the process has gone awry, say the authors.

脑动静脉畸形 (bAVM) 是动脉和静脉之间的异常连接，中间没有毛细血管。它们通常在没有任何家族史的情况下在发育过程中形成，并导致容易破裂的缠结血管。因此，bAVM 是儿童脑出血的罕见但重要的原因。虽然许多 bAVM 患者在信号因子 KRAS 的基因中存在体细胞突变，但这些突变并不能解释所有病例或完全解释病情的病理。因此，Li 及其同事对 bAVM 患者基因组和转录组进行了公正的研究，以寻找其他相关基因和途径。他们对 60 名患者及其未受影响的父母进行了全外显子组测序，并对来自 bAVM 病变的大块组织和单细胞进行了转录组分析。通过外显子组分析发现的从头突变和通过转录组分析发现的失调的 RNA 表明内皮细胞到间充质转化 (EndMT) 在 bAVM 病理学中的作用。此外，该团队还表明 KRAS 突变本身也促进了内皮细胞中的 EndMT，并且洛伐他汀药物可以防止 bAVM 患者细胞中的 EndMT。因此，这项工作不仅揭示了 EndMT 作为 bAVM 的一个特征，而且为可能的治疗提供了线索。

川崎病 (KD) 是一种全身炎症性疾病，特别影响血管，可在儿童中发展，并且没有已知的病因。严重的血管炎会导致冠状动脉瘤（CAA），这可能是致命的。KD 的标准治疗方法是静脉输注免疫球蛋白，这会降低该病症特有的炎性细胞因子 IL-1β 和 IL-18 的升高水平。然而，一些患者对这种治疗有抵抗力，与这种抵抗力相关的遗传变异表明炎症小体（调节细胞因子分泌的多蛋白复合物）发生了改变。为了更多地了解 KD 中的炎症小体-细胞因子途径，Porrit 及其同事检查了 KD 模型小鼠的发炎主动脉，发现单核细胞、巨噬细胞和树突状细胞是此类血管中 IL-1β 的主要来源，血管平滑肌细胞 (VSMC) 是可能的靶标。KD VSMCs 采用比对照血管更具迁移性和增殖性的表型，阻断 IL-1β 信号传导阻止了这种疾病表型。它还可以预防模型小鼠的心血管炎症，炎症小体抑制也是如此。因此，这项工作支持开发用于治疗 KD，尤其是免疫球蛋白耐药病例的炎症小体靶向药物。炎症小体抑制也是如此。因此，这项工作支持开发用于治疗 KD，尤其是免疫球蛋白耐药病例的炎症小体靶向药物。炎症小体抑制也是如此。因此，这项工作支持开发用于治疗 KD，尤其是免疫球蛋白耐药病例的炎症小体靶向药物。

内皮-间充质转化 (EndMT) 是一个过程，其中内皮细胞 (EC) 的特征被更具迁移性和侵袭性的成纤维细胞的特征所取代。EndMT 是器官发生的正常部分，例如在心脏瓣膜发育过程中，但也是一些疾病的病理过程，包括动脉粥样硬化、肺动脉高压和川崎病。虽然已知转录因子 SLUG 会驱动 EndMT，但促进或阻止该过程的全套分子参与者尚不清楚。现在，在人类内皮细胞中使用两种不同的 EndMT 模型 Liang 及其同事发现，转录调节因子 LARP7 在 EndMT 启动时被下调，并且内皮细胞中 LARP7 的消耗足以诱导成纤维细胞特征。染色质免疫沉淀实验进一步表明，LARP7 与 ECs 中的 SLUG 基因启动子相关联，在那里它募集了转录抑制因子 TRIM28。事实上，删除 TRIM28 也可以诱导 EndMT。最后，在心内膜缺乏 LARP7、TRIM28 或两者的小鼠胚胎中，心脏和主动脉瓣膜增厚，并伴有在对照动物中未见的过度生长迹象。这组作者说，这种对 EndMT 控制的更完整的理解应该可以提供对过程出错的疾病的见解。