title: Smad2/Smad3 in endothelium is indispensable for vascular stability via S1PR1 and N-cadherin expressions.
abstract: Transforming growth factor-β (TGF-β) 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-β signaling via Smad1/5 in ECs, ALK5 knockout (KO) mice were not able to give us the precise mechanisms by which TGF-β/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.
authors.affiliation: Department of Experimental Pathology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Fumiko
authors.initials: F
authors.lastname: Itoh
authors.forename: Susumu
authors.initials: S
authors.lastname: Itoh
authors.forename: Tomomi
authors.initials: T
authors.lastname: Adachi
authors.forename: Kei
authors.initials: K
authors.lastname: Ichikawa
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Matsumura
authors.forename: Takahiro
authors.initials: T
authors.lastname: Takagi
authors.forename: Maria
authors.initials: M
authors.lastname: Festing
authors.forename: Takuya
authors.initials: T
authors.lastname: Watanabe
authors.forename: Michael
authors.initials: M
authors.lastname: Weinstein
authors.forename: Stefan
authors.initials: S
authors.lastname: Karlsson
authors.forename: Mitsuyasu
authors.initials: M
authors.lastname: Kato
mesh_terms: D030201:Activin Receptors, Type I / Q000235:genetics / Q000378:metabolism; D030301:Activin Receptors, Type II; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics; D015820:Cadherins / Q000096:biosynthesis* / Q000235:genetics; D004727:Endothelium / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D049349:Receptors, Lysosphingolipid / Q000096:biosynthesis* / Q000235:genetics; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism*; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism*; D000081025:Sphingosine-1-Phosphate Receptors; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D000099152:Cadherin 5
chemical_list: D030201:Activin Receptors, Type I; D030301:Activin Receptors, Type II; D015703:Antigens, CD; D015820:Cadherins; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D049349:Receptors, Lysosphingolipid; D018125:Receptors, Transforming Growth Factor beta; D051899:Smad2 Protein; D051900:Smad3 Protein; D000081025:Sphingosine-1-Phosphate Receptors; D016212:Transforming Growth Factor beta; D000099152:Cadherin 5; C489083:Cdh2 protein, mouse; C556330:S1pr1 protein, mouse; C497783:Smad2 protein, mouse; C497791:Smad3 protein, mouse; C498931:Acvrl1 protein, mouse; C000625841:TGFBR1 protein, human; C000625842:Tgfbr1 protein, mouse