The transforming growth factor–β (TGF-β) and bone morphogenetic protein (BMP) family of cytokines critically regulates vascular morphogenesis and homeostasis. Impairment of TGF-β or BMP signaling leads to heritable vascular disorders, including hereditary hemorrhagic telangiectasia (HHT). Drosha, a key enzyme for microRNA (miRNA) biogenesis, also regulates the TGF-β and BMP pathway through interaction with Smads and their joint control of gene expression through miRNAs. We report that mice lacking Drosha in the vascular endothelium developed a vascular phenotype resembling HHT that included dilated and disorganized vasculature, arteriovenous fistulae, and hemorrhages. Exome sequencing of HHT patients who lacked known pathogenic mutations revealed an overrepresentation of rare nonsynonymous variants of DROSHA. Two of these DROSHA variants (P100L and R279L) did not interact with Smads and were partially catalytically active. In zebrafish, expression of these mutants or morpholino-directed knockdown of Drosha resulted in angiogenesis defects and abnormal vascular permeability. Together, our studies point to an essential role of Drosha in vascular development and the maintenance of vascular integrity, and reveal a previously unappreciated link between Drosha dysfunction and HHT.

转化生长因子-β（TGF-β）和骨形态发生蛋白（BMP）家族的细胞因子主要调节血管的形态发生和体内稳态。TGF-β或BMP信号传导受损会导致可遗传的血管疾病，包括遗传性出血性毛细血管扩张（HHT）。Drosha是microRNA（miRNA）生物发生的关键酶，它还通过与Smads相互作用以及它们通过miRNA共同控制基因表达来调节TGF-β和BMP途径。我们报告的小鼠在血管内皮中缺乏Drosha形成类似于HHT的血管表型，包括扩张和混乱的脉管系统，动静脉瘘和出血。缺乏已知病原性突变的HHT患者的外显子组测序显示，罕见的非同义变体DROSHA。这些DROSHA变体中的两个（P100L和R279L）不与Smads相互作用，并且具有部分催化活性。在斑马鱼中，这些突变体的表达或Drosha的吗啉代定向敲低导致血管生成缺陷和异常的血管通透性。总之，我们的研究指出了Drosha在血管发育和维持血管完整性中的重要作用，并揭示了Drosha功能障碍与HHT之间以前未曾认识到的联系。