C/EBPβ and Nuclear Factor of Activated T Cells Differentially Regulate Adamts-1 Induction by Stimuli Associated with Vascular Remodeling

Citations Over Time

Abstract

Emerging evidence indicates that the metalloproteinase Adamts-1 plays a significant role in the pathophysiology of vessel remodeling, but little is known about the signaling pathways that control Adamts-1 expression. We show that vascular endothelial growth factor (VEGF), angiotensin-II, interleukin-1β, and tumor necrosis factor α, stimuli implicated in pathological vascular remodeling, increase Adamts-1 expression in endothelial and vascular smooth muscle cells. Analysis of the intracellular signaling pathways implicated in this process revealed that VEGF and angiotensin-II upregulate Adamts-1 expression via activation of differential signaling pathways that ultimately promote functional binding of the NFAT or C/EBPβ transcription factors, respectively, to the Adamts-1 promoter. Infusion of mice with angiotensin-II triggered phosphorylation and nuclear translocation of C/EBPβ proteins in aortic cells concomitantly with an increase in the expression of Adamts-1, further underscoring the importance of C/EBPβ signaling in angiotensin-II-induced upregulation of Adamts-1. Similarly, VEGF promoted NFAT activation and subsequent Adamts-1 induction in aortic wall in a calcineurin-dependent manner. Our results demonstrate that Adamts-1 upregulation by inducers of pathological vascular remodeling is mediated by specific signal transduction pathways involving NFAT or C/EBPβ transcription factors. Targeting of these pathways may prove useful in the treatment of vascular disease.

Related Papers

• → Vascular endothelial growth factor B, a novel growth factor for endothelial cells.(1996)822 cited
• → Detection of Vascular Endothelial Growth Factor Messenger RNA and Vascular Endothelial Growth Factor-like Activity in Proliferative Diabetic Retinopathy(1994)363 cited
• → Systemic anti-vascular endothelial growth factor therapies induce a painful sensory neuropathy(2012)79 cited
• → Evaluation of vascular endothelial growth factor A and leukemia inhibitory factor expressions at the time of implantation in diabetic rats following treatment with Metformin and Pioglitazone(2020)3 cited
• → A disintegrin‐like and metalloproteinase with thrombospondin‐1 (ADAMTS‐1) levels in gingival crevicular fluid correlate with vascular endothelial growth factor‐A, hypoxia‐inducible factor‐1α, and clinical parameters in patients with advanced periodontitis(2019)26 cited