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Smad2/Smad3 in endothelium is indispensable for vascular stability via S1PR1 and N-cadherin expressions

Itoh, Fumiko; Itoh, Susumu; Adachi, Tomomi; Ichikawa, Kei; Matsumura, Yutaka; Takagi, Takahiro; Festing, Maria; Watanabe, Takuya; Weinstein, Michael and Karlsson, Stefan LU , et al. (2012) In Blood 119(22). p.5320-5328
Abstract
Transforming growth factor-beta (TGF-beta) is involved in vascular formation through activin receptor-like kinase (ALK)1 and ALK5. ALK5, which is expressed ubiquitously, phosphorylates Smad2 and Smad3, whereas endothelial cell (EC)-specific ALK1 activates Smad1 and Smad5. Because ALK5 kinase activity is required for ALK1 to transduce TGF-beta signaling via Smad1/5 in ECs, ALK5 knockout (KO) mice were not able to give us the precise mechanisms by which TGF-beta/ALK5/Smad2/3 signaling is implicated in angiogenesis. To delineate the role of Smad2/3 signaling in endothelium, the Smad2 gene in Smad3 KO mice was selectively deleted in ECs using Tie2-Cre transgenic mice, termed EC-specific Smad2/3 double KO (EC-Smad2/3KO) mice. EC-Smad2/3KO... (More)
Transforming growth factor-beta (TGF-beta) is involved in vascular formation through activin receptor-like kinase (ALK)1 and ALK5. ALK5, which is expressed ubiquitously, phosphorylates Smad2 and Smad3, whereas endothelial cell (EC)-specific ALK1 activates Smad1 and Smad5. Because ALK5 kinase activity is required for ALK1 to transduce TGF-beta signaling via Smad1/5 in ECs, ALK5 knockout (KO) mice were not able to give us the precise mechanisms by which TGF-beta/ALK5/Smad2/3 signaling is implicated in angiogenesis. To delineate the role of Smad2/3 signaling in endothelium, the Smad2 gene in Smad3 KO mice was selectively deleted in ECs using Tie2-Cre transgenic mice, termed EC-specific Smad2/3 double KO (EC-Smad2/3KO) mice. EC-Smad2/3KO embryos revealed hemorrhage leading to embryonic lethality around E12.5. EC-Smad2/3KO embryos exhibited no abnormality of vasculogenesis and angiogenesis in both the yolk sac and the whole embryo, whereas vascular maturation was incomplete because of inadequate assembly of mural cells in the vasculature. Wide gaps between ECs and mural cells could be observed in the vasculature of EC-Smad2/3KO mice because of reduced expression of N-cadherin and sphingosine-1-phosphate receptor-1 (S1PR1) in ECs from those mice. These results indicated that Smad2/3 signaling in ECs is indispensable for maintenance of vascular integrity via the fine-tuning of N-cadherin, VE-cadherin, and S1PR1 expressions in the vasculature. (Blood. 2012;119(22):5320-5328) (Less)
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published
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Blood
volume
119
issue
22
pages
5320 - 5328
publisher
American Society of Hematology
external identifiers
  • wos:000305291800037
  • scopus:84861810420
ISSN
1528-0020
DOI
10.1182/blood-2011-12-395772
language
English
LU publication?
yes
id
938811fc-8ce6-40bc-8de9-fd8577d3ec81 (old id 2892388)
date added to LUP
2012-08-01 08:52:10
date last changed
2017-11-12 03:16:56
@article{938811fc-8ce6-40bc-8de9-fd8577d3ec81,
  abstract     = {Transforming growth factor-beta (TGF-beta) is involved in vascular formation through activin receptor-like kinase (ALK)1 and ALK5. ALK5, which is expressed ubiquitously, phosphorylates Smad2 and Smad3, whereas endothelial cell (EC)-specific ALK1 activates Smad1 and Smad5. Because ALK5 kinase activity is required for ALK1 to transduce TGF-beta signaling via Smad1/5 in ECs, ALK5 knockout (KO) mice were not able to give us the precise mechanisms by which TGF-beta/ALK5/Smad2/3 signaling is implicated in angiogenesis. To delineate the role of Smad2/3 signaling in endothelium, the Smad2 gene in Smad3 KO mice was selectively deleted in ECs using Tie2-Cre transgenic mice, termed EC-specific Smad2/3 double KO (EC-Smad2/3KO) mice. EC-Smad2/3KO embryos revealed hemorrhage leading to embryonic lethality around E12.5. EC-Smad2/3KO embryos exhibited no abnormality of vasculogenesis and angiogenesis in both the yolk sac and the whole embryo, whereas vascular maturation was incomplete because of inadequate assembly of mural cells in the vasculature. Wide gaps between ECs and mural cells could be observed in the vasculature of EC-Smad2/3KO mice because of reduced expression of N-cadherin and sphingosine-1-phosphate receptor-1 (S1PR1) in ECs from those mice. These results indicated that Smad2/3 signaling in ECs is indispensable for maintenance of vascular integrity via the fine-tuning of N-cadherin, VE-cadherin, and S1PR1 expressions in the vasculature. (Blood. 2012;119(22):5320-5328)},
  author       = {Itoh, Fumiko and Itoh, Susumu and Adachi, Tomomi and Ichikawa, Kei and Matsumura, Yutaka and Takagi, Takahiro and Festing, Maria and Watanabe, Takuya and Weinstein, Michael and Karlsson, Stefan and Kato, Mitsuyasu},
  issn         = {1528-0020},
  language     = {eng},
  number       = {22},
  pages        = {5320--5328},
  publisher    = {American Society of Hematology},
  series       = {Blood},
  title        = {Smad2/Smad3 in endothelium is indispensable for vascular stability via S1PR1 and N-cadherin expressions},
  url          = {http://dx.doi.org/10.1182/blood-2011-12-395772},
  volume       = {119},
  year         = {2012},
}