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Crosstalk between ALK1 and Notch signaling in the vascular defects associated with HHT
Author(s) -
Kim JaiHyun,
Hughes Christopher C.W.
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.750.2
Subject(s) - notch signaling pathway , angiogenesis , signal transduction , microbiology and biotechnology , crosstalk , transcription factor , biology , receptor , gene , chemistry , cancer research , genetics , physics , optics
Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder involving the vascular system, and is caused by mutations in endoglin (HHT1) and ALK‐1 (HHT2), receptors for the TGFb/BMP family of ligands. The ALK‐5 and ALK‐1 activates the downstream Smad2/3 and Smad1/5, respectively and regulates transcription of specific genes involved in angiogenesis. Notch works in conjunction with other angiogenic pathways to pattern and stabilize the vasculature. The arterial‐venous cell fate is determined before blood circulation starts, and pathways upstream of the arterial specific marker EphrinB2 and its receptor EphB4 are involved in this process. Specifically, the Notch and TGFb‐ALK1 pathways are crucial for AV differentiation. In order to investigate the role of Notch and ALK1 on the expression of the EphrinB2 gene, we cloned the promoter region and found that NICD and ALK1 up‐regulate the EphrinB2 promoter synergistically. A single RBP site is required for notch activity and the promoter also contains multiple TGFb/BMP response elements. We have also investigated the role of ALK1 in EC sprout formation using an in vitro angiogenesis model and find that ALK1 knock down disrupts normal sprout formation. These data support the concept of functional interaction between Notch signaling and BMP/ALK1 signaling. This work was supported by the HHT Foundation International.