ALK1 Signaling Inhibits Angiogenesis by Cooperating with the Notch Pathway

被引：301

作者：

Larrivee, Bruno ^{[1
]}

Prahst, Claudia ^{[1
]}

Gordon, Emma ^{[1
]}

del Toro, Raquel ^{[2
]}

Mathivet, Thomas ^{[2
]}

Duarte, Antonio ^{[3
]}

Simons, Michael ^{[1
,4
]}

Eichmann, Anne ^{[1
,2
]}

机构：

[1] Yale Univ, Sch Med, Dept Internal Med, Yale Cardiovasc Res Ctr,Sect Cardiovasc Med, New Haven, CT 06511 USA

[2] CIRB Coll France, CNRS, INSERM, U1050,UMR7241, F-75005 Paris, France

[3] Univ Tecn Lisboa, Ctr Interdisciplinar Invest Sanidade Anim, Fac Med Vet, P-1300477 Lisbon, Portugal

[4] Yale Univ, Dept Cell Biol, Sch Med, New Haven, CT 06520 USA

来源：

DEVELOPMENTAL CELL | 2012年 / 22卷 / 03期

关键词：

HEREDITARY HEMORRHAGIC TELANGIECTASIA; TIP CELL-FORMATION; ARTERIOVENOUS-MALFORMATIONS; VASCULAR DEVELOPMENT; RECEPTOR; ACTIVATION; EXPRESSION; VEGF; DLL4; IDENTIFICATION;

D O I：

10.1016/j.devcel.2012.02.005

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Activin receptor-like kinase 1 (ALK1) is an endothelial-specific member of the TGF-beta/BMP receptor family that is inactivated in patients with hereditary hemorrhagic telangiectasia (HHT). How ALK1 signaling regulates angiogenesis remains incompletely understood. Here we show that ALK1 inhibits angiogenesis by cooperating with the Notch pathway. Blocking Alk1 signaling during postnatal development in mice leads to retinal hypervascularization and the appearance of arteriovenous malformations (AVMs). Combined blockade of Alk1 and Notch signaling further exacerbates hypervascularization, whereas activation of Alk1 by its high-affinity ligand BMP9 rescues hypersprouting induced by Notch inhibition. Mechanistically, ALK1-dependent SMAD signaling synergizes with activated Notch in stalk cells to induce expression of the Notch targets HEY1 and HEY2, thereby repressing VEGF signaling, tip cell formation, and endothelial sprouting. Taken together, these results uncover a direct link between ALK1 and Notch signaling during vascular morphogenesis that may be relevant to the pathogenesis of HHT vascular lesions.

引用

页码：489 / 500

页数：12

共 62 条

[41] Endothelial Notch signaling is upregulated in human brain arteriovenous malformations and a mouse model of the disease [J].