Alk2/ACVR1 and Alk3/BMPR1A Provide Essential Function for Bone Morphogenetic Protein-Induced Retinal Angiogenesis

被引:35
|
作者
Lee, Heon-Woo [1 ]
Chong, Diana C. [2 ,3 ]
Ola, Roxana [1 ]
Dunworth, William P. [1 ]
Meadows, Stryder [4 ,8 ]
Ka, Jun [5 ,6 ]
Kaartinen, Vesa M. [7 ]
Qyang, Yibing [1 ]
Cleaver, Ondine [4 ]
Bautch, Victoria L. [2 ,3 ]
Eichmann, Anne [1 ]
Jin, Suk-Won [1 ,5 ,6 ]
机构
[1] Yale Univ, Sch Med, Dept Internal Med, Yale Cardiovasc Res Ctr,Sect Cardiovasc Med, New Haven, CT 06510 USA
[2] Univ N Carolina, Dept Biol, Chapel Hill, NC 27599 USA
[3] Univ N Carolina, McAllister Heart Inst, Chapel Hill, NC 27599 USA
[4] UT Southwestern Med Ctr, Dept Mol Biol, Dallas, TX USA
[5] Gwangju Inst Sci & Technol, Sch Life Sci, Gwangju, South Korea
[6] Gwangju Inst Sci & Technol, Cell Logist Res Ctr, Gwangju, South Korea
[7] Univ Michigan, Sch Dent, Dept Biol & Mat Sci, Ann Arbor, MI 48109 USA
[8] Tulane Univ, Dept Cell & Mol Biol, New Orleans, LA 70118 USA
基金
新加坡国家研究基金会; 美国国家卫生研究院;
关键词
angiogenesis; BMP signaling; retina; vertebrate development; KINASE; 1; ALK1; MOUSE EMBRYOGENESIS; I RECEPTORS; IDENTIFICATION; GASTRULATION; CELLS; NOTCH; BMP9; DIFFERENTIATION; ROLES;
D O I
10.1161/ATVBAHA.116.308422
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Objective-Increasing evidence suggests that bone morphogenetic protein (BMP) signaling regulates angiogenesis. Here, we aimed to define the function of BMP receptors in regulating early postnatal angiogenesis by analysis of inducible, endothelial-specific deletion of the BMP receptor components Bmpr2 (BMP type 2 receptor), Alk1 (activin receptor-like kinase 1), Alk2, and Alk3 in mouse retinal vessels. Approach and Results-Expression analysis of several BMP ligands showed that proangiogenic BMP ligands are highly expressed in postnatal retinas. Consistently, BMP receptors are also strongly expressed in retina with a distinct pattern. To assess the function of BMP signaling in retinal angiogenesis, we first generated mice carrying an endothelial-specific inducible deletion of Bmpr2. Postnatal deletion of Bmpr2 in endothelial cells substantially decreased the number of angiogenic sprouts at the vascular front and branch points behind the front, leading to attenuated radial expansion. To identify critical BMPR1s (BMP type 1 receptors) associated with BMPR2 in retinal angiogenesis, we generated endothelial-specific inducible deletion of 3 BMPR1s abundantly expressed in endothelial cells and analyzed the respective phenotypes. Among these, endothelial-specific deletion of either Alk2/acvr1 or Alk3/Bmpr1a caused a delay in radial expansion, reminiscent of vascular defects associated with postnatal endothelial-specific deletion of BMPR2, suggesting that ALK2/ACVR1 and ALK3/BMPR1A are likely to be the critical BMPR1s necessary for proangiogenic BMP signaling in retinal vessels. Conclusions-Our data identify BMP signaling mediated by coordination of ALK2/ACVR1, ALK3/BMPR1A, and BMPR2 as an essential proangiogenic cue for retinal vessels.
引用
收藏
页码:657 / 663
页数:7
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