Abstract Body:
Introduction:
The lipokine 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME) is a known systemic regulator of energy homeostasis. Previous research from our laboratory established 12,13-diHOME as a cold- and exercise-induced signal that enhances skeletal muscle fatty acid uptake and improves cardiac function. Its levels are markedly reduced in humans with obesity or heart failure.
In a healthy state, PVAT maintains vascular tone through the secretion of adipose-tissue derived relaxation factors (ADRFs), but this protective mechanism is lost in obesity, driving vascular dysfunction and cardiovascular disease (CVD). Despite its presence in the PVAT-vascular axis, the specific molecular targets, acute and chronic effects of 12,13-diHOME on vascular axis remain unexplored. We hypothesized that increasing 12,13-diHOME could be protective molecule against impaired vascular function in obesity.

Methods:
Thoracic aorta was assessed via wire myography in WT and DIO mice to determine the ex-vivo vascular effects of 12,13-diHOME. Isolated and PVAT cleaned thoracic aorta acutely treated with 12,13-diHOME for western blot studies.

Results:
Wire myography revealed that 12,13-diHOME acts as a vasodilator on aorta and its effect independent of sex. Incubation with 12,13-diHOME resulted in a 40% dilation on PVAT- aorta and an enhanced and sustained dilative response in PVAT+ aorta, suggesting that 12,13-diHOME stimulates the PVAT further to dilate the aorta (60-80%). Acute incubation with 100nM 12,13-diHOME (4 min) increased p-AMPK/AMPK in PVAT- aorta ex vivo, corresponding with the rapid dilative response that we observe in wire myography.

Conclusions:
These data identify 12,13-diHOME as a potent vasodilator of the thoracic aorta. The amplified relaxant response in the presence of PVAT, coupled with rapid pAMPK, suggests that 12,13-diHOME acts through the PVAT-vascular axis. Given its reduction in obesity, 12,13-diHOME represents a promising therapeutic target for restoring vascular homeostasis and counteracting obesity-induced cardiovascular dysfunction.