Objective: Perivascular adipose tissue (PVAT) has an anticontractile effect which is lost in obesity and the metabolic syndrome leading to hypertension associated cardiovascular complications (1). cGMP dependent protein kinase has been implicated in as a key molecule in regulating vascular tone (2), furthermore obesity the intake of a high fat diet is associated with a reduction in PKG expression (3). We investigated the role of cGMP dependent protein kinase (PKG) in PVAT function specifically in modulating adipokine release/signalling and whether activation of PKG is beneficial using an in vitro model of obesity. Methods: Contractility of mesenteric arteries±PVAT from PKG+/+, PKG-/-, adiponectin-/- knockout and C57/Bl6J mice was investigated by wire myography. All procedures were performed in accord with current UK legislation. Vessels were studied under normoxia +/- DT-2 (PKG1α peptide selective inhibitor) (125nM), hypoxia (95% N2/ 5%O2)± atrial natriuretic peptide (ANP) (5µM). Contractile responses to noradrenaline (NA) (1×10-5M to 3×10-9M) were calculated as a percentage of KCl (60mM) contraction, and expressed as mean±SEM. Expression of adiponectin was assessed by immunohistochemistry. Results: Healthy PVAT had an anticontractile effect which was absent in PKG-/- mice and following pharmacological inhibition of PKG signalling (PVAT vs. no PVAT: PKG+/+: P<0.001 n=13; PKG-/-: P=0.052, n=13; DT-2: P=0.071, n=8). Solution transfer studies between preconstricted (3×10-8M NA) PKG+/+ (+PVAT) donor arteries to PKG-/- (-PVAT) recipient arteries and PKG-/- (+PVAT) donor arteries to PKG+/+ (-PVAT) recipient arteries were associated with a significantly impaired relaxation compared with PKG+/+ +PVAT to PKG+/+ -PVAT solution transfer (P=0.023 and P=0.043 respectively, n=13). Experimental hypoxia in PKG+/+ induced a loss of PVAT associated anticontractile effect which was prevented by ANP (PVAT+normoxia vs. PVAT+hypoxia: P=0.0157, n=10; PVAT+hypoxia vs. PVAT+hypoxia+ANP P=0.0093, n=8) No significant effects of hypoxia +/- ANP were observed in PKG-/- animals. Furthermore, the loss of anticontractile effect observed in adiponectin-/- mice was not affected by hypoxia and could not be rescued by ANP (no PVAT vs PVAT: P=0.1486, n=6; PVAT vs. PVAT+hypoxia: P=0.6507, n=6; PVAT+hypoxia vs. PVAT+hypoxia+ANP: P=0.1538, n=6). Immunohistochemical detection of adiponectin demonstrated reduced adiponectin following hypoxia, which was prevented when ANP was present. Conclusions: Our data implicate PKG signalling in mediating PVAT function both up and down stream of secreted adipose tissue factor(s) through its role in mediating the expression and signalling of adiponectin. Investigations in obesity are necessary to confirm the role of PKG in PVAT dysfunction.