Abstract Body: Lipoprotein metabolism plays a role in cardiovascular diseases and becomes impaired with aging. Angiopoietin-like proteins (ANGPTLs) regulate lipoprotein lipase (LPL) and endothelial lipase (EL), key hydrolases in triglyceride catabolism. We hypothesized that ANGPTL3 and ANGPTL4 would be elevated in aging and that the response to LPL activation would be impaired in mesenteric resistance arteries (MRAs) from old rats. To assess this, MRAs were isolated from 3 and 16-month-old male and female Fischer344 rats and mounted on wire myographs. Concentration-response curves (CRC) to phenylephrine (PE, 10nM-100μM), Ca²⁺ channel agonist Bay-K8644 (10nM-30nM), and acetylcholine (ACh, 0.1nM-100uM) were performed with or without LPL activator, NO-1886 (10uM and 50uM). Protein expression was assessed by Western blot. We show for the first time that circulating ANGPTL3 (young: 1.5±0.8 vs old: 5±0.7) and ANGPTL4 (young: 1.7±0.3 vs old: 2.5±0.5) are increased in aging. In MRAs from young rats, NO-1886 attenuated PE-induced contraction in males (Emax; vehicle: 106±3 vs NO-1886 10uM: 86 ± 5* vs NO-1886 50uM: 69±8*, p<0.05) and females (Emax; vehicle: 104±4 vs NO-1886 10uM: 91±5* vs NO-1886 50uM: 75±8*, p<0.05). While 16-month-old males presented a similar reduction in contraction (Emax; vehicle: 105±6 vs NO-1886 10uM: 88±11* vs NO-1886 50uM: 73±17*, p<0.05), in females only 50uM showed a significant anti-contractile effect in a sex-dependent manner (Emax; vehicle: 100±7 vs NO-1886 10uM: 95±7 vs NO-1886 50uM: 83±22*, p<0.05). CRC to bay-K8644 showed decreased contraction after NO-1886 incubation (Emax; vehicle: 16±8 vs NO-1886 50uM: 5±3) indicating that L-type Ca²⁺ channel Ca²⁺ influx isn’t involved in NO-1886’s anti-contractile effect. NO-1886 incubation did not change the maximal ACh response in young rat MRAs, but a rightward shift in the curve was seen in both sexes. As expected, MRAs from old males (Emax; young: 97±2 vs old: 86±7) and females (Emax; young: 95±2 vs old: 92±6) had decreased maximal relaxation to ACh, compared to young rats. Interestingly, in old rats NO-1886 induced further impaired relaxation to ACh in males (Emax; vehicle: 86±7 vs NO-1886 10uM: 78±14) and females (Emax; vehicle: 92±6 vs NO-1886 10uM: 77±22). Together, this data suggests (1) ANGPTL3 and ANGPTL4 are increased in old rats, (2) LPL/EL activity diminished with age in females, but not males, and (3) while NO-1886 exerts an anti-contractile effect, it can also induce endothelial dysfunction.