Dysregulated Hepatic Autophagy Drives ANGPTL4 Overexpression and Exacerbates Hypertensive Vascular Dysfunction

Autophagy, a crucial process for maintaining cellular homeostasis, is inversely associated with premature vascular aging in hypertension. Angiopoietin-like protein 4 (ANGPTL4) is a key regulator of lipoprotein metabolism via inhibition of lipoprotein lipase (LPL) and endothelial lipase (EL) and has been implicated as an important regulator of atherosclerosis. However, it is unknown whether it plays a role in total peripheral resistance and hypertension. We hypothesized that diminished hepatic autophagy increases ANGPTL4 biosynthesis, thereby contributing to vascular dysfunction. To test this, hepatic ANGPTL4 expression was analyzed in autophagy-deficient Atg5 KO mice, while hepatic autophagy was assessed via SQSTM1/p62 in BPH/2J hypertensive mice compared to normotensive BPN/3J controls. Circulating ANGPTL4 levels were also measured. Vascular function was assessed on mesenteric resistance arteries (MRA) to determine the effects of NO-1886, an EL/LPL activator, and recombinant ANGPTL4 (rANGPTL4). Our findings demonstrated that autophagy deficiency significantly increased hepatic ANGPTL4 expression (WT: 0.28±0.01 vs. KO: 0.36±0.01*, * p <0.05). Usually, enhanced autophagic activity reduces SQSTM1/p62 levels, whereas inhibition of autophagy results in their accumulation. Consistent with this, hypertensive BPH/2J mice exhibited reduced autophagic activity, as evidenced by elevated hepatic SQSTM1/p62 levels compared to normotensive BPN/3J controls (BPN/3J: 0.60±0.10 vs. BPH/2J: 1.17±0.34*, * p <0.05). Circulating ANGPTL4 was higher in BPH/2J mice (BPN/3J: 2.26±0.21 vs. BPH/2J: 3.30±0.31*, *p<0.05). Functional studies in isolated MRA showed that NO-1886 exerted a concentration-dependent anti-contractile effect on phenylephrine-induced MRA contraction, which was partially reversed by L-NAME (Veh: 120±3 vs. NO-1886 (50 µM): 48±3* vs. NO-1886+L-NAME: 90±5 # , * # p <0.05). Furthermore, pre-incubation with rANGPTL4 enhanced the contractile response to phenylephrine in MRAs of WT animals, highlighting the pro-contractile role of ANGPTL4 in vascular tone regulation. These results establish a mechanistic link between impaired hepatic autophagy and ANGPTL4 overexpression, driving vascular dysfunction in hypertension. Targeted inhibition of ANGPTL4 may represent a novel therapeutic strategy to improve vascular health in hypertensive patients. Additionally, the modulation of vascular contractility by EL/LPL activation suggests promising avenues for addressing vascular dysfunction in hypertension. NHLBI R56HL169223 NHLBI R00HL151889 NIH SCORE Improving awareness of women with hypertension: ROAR (U54HL169191) USC of Research ASPIRE Award (180950-23-64136) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.