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Endothelial ARF6 deletion impairs insulin‐induced dilation of adipose arteries and systemic glucose tolerance
Author(s) -
Breevoort Sarah,
Henson Grant,
Gibson Chris,
Reihl Kelly,
Li Dean,
Donato Anthony,
Lesniewski Lisa
Publication year - 2015
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.29.1_supplement.802.1
Subject(s) - medicine , endocrinology , vasodilation , sodium nitroprusside , endothelial dysfunction , nitric oxide , endothelium , insulin , bradykinin , adipose tissue , chemistry , receptor
Adipose tissue (AT) function is an important determinant of metabolic homeostasis and healthy AT requires appropriate function of its arterial endothelium to regulate tissue blood flow and limit inflammation. Signaling through the GTPase, ARF6, has been shown to modulate endothelial nitric oxide (NO) production, angiogenesis and leukocyte adhesion. As such, endothelial (ec) ARF6 may be critical for the regulation of arterial function within the AT and, subsequently, for systemic metabolic function. Insulin‐induced endothelium dependent vasodilation was impaired (8 ± 2 vs. 37 ± 7%, P<0.01) and NO bioavailability reduced (1 ± 1 vs. 20 ± 7%, P<0.01) in isolated AT arteries from ecARF6 knockout (ecARF6 ‐/‐ ) mice compared to wildtype (WT) controls despite intact vasodilation to acetylcholine (P>0.05). Dilation to sodium nitroprusside was not different between groups (P>0.05). AT vascularity, assessed by PECAM immunofluorescence, was reduced ~40% and AT superoxide production, measured by electron magnetic resonance, was increased ~5 fold in ecARF6 ‐/‐ mice compared to WT (both P<0.05). In cultured endothelial cells, siRNA‐mediated ARF6 deletion increased leukocyte rolling/adhesion ~2 fold (P<0.05). Concomitantly, ecARF6 deletion resulted in metabolic dysfunction, as ecARF ‐/‐ mice were glucose intolerant (P<0.05) compared to WT. These findings suggest that loss of ecARF6 leads to impairments in insulin signaling in the AT artery endothelium, reductions in the vascularity of the AT and promotion of a pro‐inflammatory environment that contributes to systemic metabolic dysfunction.