Journal
SCIENCE TRANSLATIONAL MEDICINE
Volume 11, Issue 510, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.aav5055
Keywords
-
Categories
Funding
- British Heart Foundation [FS/16/15/32047, PG/13/56/30383, CH/16/1/32013, RG/13/1/30181, FS/16/45/32359]
- National Institute for Health Research Oxford Biomedical Research Centre
- European commission (ITN network RADOX)
- Novo Nordisk Foundation [NNF15CC0018486]
- Alexander S. Onassis Public Benefit Foundation
- Wellcome Trust [090532/Z/09/Z]
- Novo Nordisk Postdoctoral Fellowship
- University of Oxford
- EPSRC [2119518] Funding Source: UKRI
Ask authors/readers for more resources
Obesity is associated with changes in the secretome of adipose tissue (AT), which affects the vasculature through endocrine and paracrine mechanisms. Wingless-related integration site 5A (WNT5A) and secreted frizzled-related protein 5 (SFRP5), adipokines that regulate noncanonical Wnt signaling, are dysregulated in obesity. We hypothesized that WNT5A released from AT exerts endocrine and paracrine effects on the arterial wall through noncanonical RAC1-mediated Wnt signaling. In a cohort of 1004 humans with atherosclerosis, obesity was associated with increased WNT5A bioavailability in the circulation and the AT, higher expression of WNT5A receptors Frizzled 2 and Frizzled 5 in the human arterial wall, and increased vascular oxidative stress due to activation of NADPH oxidases. Plasma concentration of WNT5A was elevated in patients with coronary artery disease compared to matched controls and was independently associated with calcified coronary plaque progression. We further demonstrated that WNT5A induces arterial oxidative stress and redox-sensitive migration of vascular smooth muscle cells via Frizzled 2-mediated activation of a previously uncharacterized pathway involving the deubiquitinating enzyme ubiquitin-specific protease 17 (USP17) and the GTPase RAC1. Our study identifies WNT5A and its downstream vascular signaling as a link between obesity and vascular disease pathogenesis, with translational implications in humans.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available