Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06511, USA.
Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Nat Commun. 2016 Nov 29;7:13650. doi: 10.1038/ncomms13650.
Activin receptor-like kinase 1 (ALK1) is an endothelial serine-threonine kinase receptor for bone morphogenetic proteins (BMPs) 9 and 10. Inactivating mutations in the ALK1 gene cause hereditary haemorrhagic telangiectasia type 2 (HHT2), a disabling disease characterized by excessive angiogenesis with arteriovenous malformations (AVMs). Here we show that inducible, endothelial-specific homozygous Alk1 inactivation and BMP9/10 ligand blockade both lead to AVM formation in postnatal retinal vessels and internal organs including the gastrointestinal (GI) tract in mice. VEGF and PI3K/AKT signalling are increased on Alk1 deletion and BMP9/10 ligand blockade. Genetic deletion of the signal-transducing Vegfr2 receptor prevents excessive angiogenesis but does not fully revert AVM formation. In contrast, pharmacological PI3K inhibition efficiently prevents AVM formation and reverts established AVMs. Thus, Alk1 deletion leads to increased endothelial PI3K pathway activation that may be a novel target for the treatment of vascular lesions in HHT2.
激活素受体样激酶 1 (ALK1) 是骨形态发生蛋白 (BMP) 9 和 10 的内皮丝氨酸-苏氨酸激酶受体。ALK1 基因的失活突变导致遗传性出血性毛细血管扩张症 2 型 (HHT2)，这是一种致残性疾病，其特征是过度血管生成伴动静脉畸形 (AVM)。在这里，我们表明，诱导性、内皮特异性纯合 Alk1 失活和 BMP9/10 配体阻断都会导致小鼠出生后视网膜血管和内部器官（包括胃肠道 (GI) 道）中的 AVM 形成。ALK1 缺失和 BMP9/10 配体阻断会增加 VEGF 和 PI3K/AKT 信号转导。信号转导 Vegfr2 受体的基因缺失可防止过度血管生成，但不能完全逆转 AVM 的形成。相比之下，药理学 PI3K 抑制可有效防止 AVM 的形成并逆转已建立的 AVM。因此，ALK1 缺失导致内皮 PI3K 通路的激活增加，这可能是 HHT2 血管病变治疗的新靶点。
