Aims BMP9 is a high affinity ligand of ALK1 and endoglin receptors that are mutated in the rare genetic vascular disorder Hereditary Hemorrhagic Telangiectasia (HHT). We have previously shown that loss of Bmp9 in the 129/Ola genetic background leads to spontaneous liver fibrosis via capillarization of liver sinusoidal endothelial cells (LSEC) and kidney lesions. We aimed to decipher the molecular mechanisms downstream of BMP9 to better characterize its role in vascular homeostasis in different organs. Methods and results For this, we performed a RNAseq analysis on LSEC from adult WT and Bmp9-KO mice and identified over 2000 differentially expressed genes. Gene ontology analysis showed that Bmp9 deletion led to a decrease in BMP and Notch signaling, but also LSEC capillary identity while increasing their cell cycle. The gene ontology term “glomerulus development” was also negatively enriched in Bmp9-KO mice versus WT supporting a role for BMP9 in kidney vascularization. Through different imaging approaches (electron microscopy, immunostainings), we found that loss of Bmp9 led to vascular enlargement of the glomeruli capillaries associated with alteration of podocytes. Importantly, we also showed for the first time that the loss of Bmp9 led to spontaneous arteriovenous malformations (AVMs) in the liver, gastro-intestinal tract and uterus. Conclusions Altogether, these results demonstrate that BMP9 plays an important role in vascular quiescence both locally in the liver by regulating endothelial capillary differentiation markers and cell cycle but also at distance in many organs via its presence in the circulation. It also reveals that loss of Bmp9 is sufficient to induce spontaneous AVMs, supporting a key role for BMP9 in the pathogenesis of HHT.

中文翻译：

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BMP9 是内皮特性的关键参与者，其缺失足以诱发动静脉畸形

目标 BMP9 是 ALK1 和内皮糖蛋白受体的高亲和力配体，这些受体在罕见的遗传性血管疾病遗传性出血性毛细血管扩张症 (HHT) 中发生突变。我们之前已经表明，129/Ola 遗传背景中 Bmp9 的缺失会通过肝窦内皮细胞 (LSEC) 毛细血管化和肾脏病变导致自发性肝纤维化。我们的目的是破译 BMP9 下游的分子机制，以更好地表征其在不同器官血管稳态中的作用。方法和结果 为此，我们对成年 WT 和 Bmp9-KO 小鼠的 LSEC 进行了 RNAseq 分析，并鉴定了 2000 多个差异表达基因。基因本体分析表明，Bmp9 缺失导致 BMP 和 Notch 信号传导减少，而且 LSEC 毛细血管特性减少，同时细胞周期增加。与 WT 小鼠相比，基因本体论术语“肾小球发育”在 Bmp9-KO 小鼠中也呈负富集，支持 BMP9 在肾血管形成中的作用。通过不同的成像方法（电子显微镜、免疫染色），我们发现 Bmp9 的缺失导致与足细胞改变相关的肾小球毛细血管扩张。重要的是，我们还首次证明 Bmp9 的缺失会导致肝脏、胃肠道和子宫的自发性动静脉畸形 (AVM)。结论 总而言之，这些结果表明，BMP9 在肝脏局部通过调节内皮毛细血管分化标记物和细胞周期在血管静止中发挥着重要作用，而且在许多器官中通过其存在于循环中而在远处发挥着重要作用。它还表明，Bmp9 的缺失足以诱导自发性 AVM，支持 BMP9 在 HHT 发病机制中的关键作用。