Abstract:
RATIONALE:Activin receptor-like kinase-1 (ALK1) is an endothelial transforming growth factor β receptor involved in angiogenesis. ALK1 expression is high in the embryo vasculature, becoming less detectable in the quiescent endothelium of adult stages. However, ALK1 expression becomes rapidly increased after angiogenic stimuli such as vascular injury. OBJECTIVE:To characterize the molecular mechanisms underlying the regulation of ALK1 on vascular injury. METHODS AND RESULTS:Alk1 becomes strongly upregulated in endothelial (EC) and vascular smooth muscle cells of mouse femoral arteries after wire-induced endothelial denudation. In vitro denudation of monolayers of human umbilical vein ECs also leads to an increase in ALK1. Interestingly, a key factor in tissue remodeling, Krüppel-like factor 6 (KLF6) translocates to the cell nucleus during wound healing, concomitantly with an increase in the ALK1 gene transcriptional rate. KLF6 knock down in human umbilical vein ECs promotes ALK1 mRNA downregulation. Moreover, Klf6(+/-) mice have lower levels of Alk1 in their vasculature compared with their wild-type siblings. Chromatin immunoprecipitation assays show that KLF6 interacts with ALK1 promoter in ECs, and this interaction is enhanced during wound healing. We demonstrate that KLF6 is transactivating ALK1 gene, and this transactivation occurs by a synergistic cooperative mechanism with specificity protein 1. Finally, Alk1 levels in vascular smooth muscle cells are not directly upregulated in response to damage, but in response to soluble factors, such as interleukin 6, released from ECs after injury. CONCLUSIONS:ALK1 is upregulated in ECs during vascular injury by a synergistic cooperative mechanism between KLF6 and specificity protein 1, and in vascular smooth muscle cells by an EC-vascular smooth muscle cell paracrine communication during vascular remodeling.
journal_name
Circ Resjournal_title
Circulation researchauthors
Garrido-Martín EM,Blanco FJ,Roquè M,Novensà L,Tarocchi M,Lang UE,Suzuki T,Friedman SL,Botella LM,Bernabéu Cdoi
10.1161/CIRCRESAHA.112.275586subject
Has Abstractpub_date
2013-01-04 00:00:00pages
113-27issue
1eissn
0009-7330issn
1524-4571pii
CIRCRESAHA.112.275586journal_volume
112pub_type
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