Abstract Body: The pathogenesis of hypertension (HTN) involves dysregulated inflammatory responses and structural remodeling of the vasculature, including its perivascular adipose tissue (PVAT). Oxylipins (OXL), lipid-derived inflammatory mediators, regulate remodeling processes in various organs; however, their dynamics in HTN remain poorly defined. Using the Dahl salt-sensitive rat model, we assessed shifts in plasma OXL profiles and transcriptional changes in OXL-related gene networks within PVAT. Plasma and thoracic PVAT samples were collected from 10 male (M) and 10 female (F) rats fed either a control (CON; n = 5 M, 5 F) or high-fat (HF; 60% kcal from saturated fat; n = 5 M, 5 F) diet for 24 weeks. OXL levels were quantified by targeted HPLC-MS/MS (64 OXLs). Significance was defined as P < 0.05 and fold change >|1.5|. Gene expression was evaluated using snRNA-seq and pathway analysis was performed via Ingenuity Pathway Analysis (IPA), incorporating OXL data to predict upstream gene network activity. HF feeding increased mean arterial pressure by ≥25 mmHg vs. CON. Plasma levels of 18-HEPE, TXB2, PGE2, Resolvin D4, and Protectin Dx were reduced in HF vs. CON rats. M had higher 15-epi-lipoxin A4 levels than F. CON M had lower Protectin D1 and Resolvin D5 vs. CON F. HF M had reduced Protectin D1 and Resolvin D4 vs. CON M. HF F had lower 12-HDoHE vs. CON F. Based on OXL profiles, IPA predicted involvement of phospholipases (Pla-), lipoxygenases (Alox-), solute carriers (Slc-), and angiotensinogen pathways, and the HTN-associated inflammatory gene netrin-1 (Ntn1). snRNA-seq data were used to assess transcriptional regulation of these network components in specific PVAT cell types. In PVAT adipocytes, Slc40a1 expression was higher in HF vs. CON, whereas Ntn1 was downregulated across all PVAT cell types in HF vs. CON. M had lower expression of Slc40a1 and Ntn1 vs. F across cell populations. Angiotensinogen (Agt) expression was specifically reduced in PVAT brown adipocytes of HF M vs. HF F. These findings suggest that in established HTN (24 weeks of HF feeding), anti-inflammatory (resolvins) and anti-hypertensive (18-HEPE) OXL levels in M and F are diminished. This reduction coincides with lower expression of Ntn1 and the iron exporter Slc40a1, implicating PVAT in HTN pathogenesis via dysregulation of genes involved in anti-inflammatory OXL synthesis.