Research ArticleCARDIOMETABOLIC DISEASE

Adipose tissue–derived WNT5A regulates vascular redox signaling in obesity via USP17/RAC1-mediated activation of NADPH oxidases

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Science Translational Medicine  18 Sep 2019:
Vol. 11, Issue 510, eaav5055
DOI: 10.1126/scitranslmed.aav5055

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Adiposity and artery disease

Obesity is a risk factor for cardiovascular disease. Akoumianakis and colleagues studied the link between obesity and atherosclerosis, finding that adipokines that regulate noncanonical Wnt signaling were dysregulated. Patients who were obese and those with coronary artery disease had high amounts of plasma WNT5A, which was associated with progression of calcified plaques. Mechanistically, WNT5A secreted by perivascular adipose tissue induced oxidative stress in blood vessel walls and migration of smooth muscle cells. This study helps shed light on the interaction between adipose tissue and blood vessels and identifies a potential therapeutic target for cardiometabolic disease.

Abstract

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.

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