Alk2/ACVR1 and Alk3/BMPR1A provide essential function for bone morphogenetic protein-induced retinal angiogenesis

Heon Woo Lee, Diana C. Chong, Roxana Ola, William P. Dunworth, Stryder Meadows, Jun Ka, Vesa M. Kaartinen, Yibing Qyang, Ondine Cleaver, Victoria L. Bautch, Anne Eichmann, Suk Won Jin

Research output: Contribution to journalArticle

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Abstract

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.

LanguageEnglish (US)
Pages657-663
Number of pages7
JournalArteriosclerosis, thrombosis, and vascular biology
Volume37
Issue number4
DOIs
StatePublished - Jan 1 2017

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Bone Morphogenetic Proteins
Bone Morphogenetic Protein Receptors
Retinal Vessels
Blood Vessels
Retina
Type I Bone Morphogenetic Protein Receptors
Type II Bone Morphogenetic Protein Receptors
Endothelial Cells
Activin Receptors
Ligands
Cues
Phenotype

Keywords

  • Angiogenesis
  • BMP signaling
  • Retina
  • Vertebrate development

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Alk2/ACVR1 and Alk3/BMPR1A provide essential function for bone morphogenetic protein-induced retinal angiogenesis. / Lee, Heon Woo; Chong, Diana C.; Ola, Roxana; Dunworth, William P.; Meadows, Stryder; Ka, Jun; Kaartinen, Vesa M.; Qyang, Yibing; Cleaver, Ondine; Bautch, Victoria L.; Eichmann, Anne; Jin, Suk Won.

In: Arteriosclerosis, thrombosis, and vascular biology, Vol. 37, No. 4, 01.01.2017, p. 657-663.

Research output: Contribution to journalArticle

Lee, HW, Chong, DC, Ola, R, Dunworth, WP, Meadows, S, Ka, J, Kaartinen, VM, Qyang, Y, Cleaver, O, Bautch, VL, Eichmann, A & Jin, SW 2017, 'Alk2/ACVR1 and Alk3/BMPR1A provide essential function for bone morphogenetic protein-induced retinal angiogenesis' Arteriosclerosis, thrombosis, and vascular biology, vol. 37, no. 4, pp. 657-663. DOI: 10.1161/ATVBAHA.116.308422
Lee, Heon Woo ; Chong, Diana C. ; Ola, Roxana ; Dunworth, William P. ; Meadows, Stryder ; Ka, Jun ; Kaartinen, Vesa M. ; Qyang, Yibing ; Cleaver, Ondine ; Bautch, Victoria L. ; Eichmann, Anne ; Jin, Suk Won. / Alk2/ACVR1 and Alk3/BMPR1A provide essential function for bone morphogenetic protein-induced retinal angiogenesis. In: Arteriosclerosis, thrombosis, and vascular biology. 2017 ; Vol. 37, No. 4. pp. 657-663
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AU - Dunworth,William P.

AU - Meadows,Stryder

AU - Ka,Jun

AU - Kaartinen,Vesa M.

AU - Qyang,Yibing

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AB - 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.

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