LAUSR

Hepatokines, defined as proteins or protein-like substances secreted mainly or exclusively by the liver in an endocrine or paracrine way, play an essential role in modulating the metabolic progress and pathological conditions of the body. While it is well known that hepatokines play a major pro-inflammatory role in the body, it is still unclear as to whether their actions specifically affect vascular function. We hypothesized that some, if not all, hepatokines would play a role in vasoconstriction in mesenteric resistance arteries (MRA) of male Wistar rats (12 weeks old, n=4-17). To test this hypothesis, we isolated and mounted MRA with endothelium in a wire myography. After evaluating vascular viability, arteries were treated with hepatokine (1 μg/mL) or vehicle for 30 minutes. This was done for a total of 15 different hepatokines: ANGPTL3, ANGPTL4, ANGPTL6, ANGPTL8, Fetuin-A, FGF21, Follistatin, GDF-15, Hepassocin, IGF-1, LECT2, Lipocalin-13, SEPP1, SMOC-1, and Tsukushi. Subsequently, we performed concentration-response curves to phenylephrine (10-9 to 10-4 M) and used maximal response and LogEC50 to compare the contraction response curve of the MRA bathed in hepatokine to the control (vehicle). Interestingly, the hepatokines ANGPTL3 [% KCl 120mM, Vehicle: 132.1±3.2 vs. ANGPTL3: 141.6±3.9, p=0.0540] (figure a), FGF21 [% KCl 120mM, Vehicle: 123.3±5.8 vs. FGF21: 139.7±4.8, p=0.0355] (figure d), and ANGPTL4 [% KCl 120mM, Vehicle: 130.2±3.6 vs. ANGPTL4: 141.7±3.7, p=0.0282] (figure b) increased maximum contraction, while the hepatokines SMOC-1 [LogEC50, Vehicle: -5.7±0.1 vs. SMOC-1: -6.0±0.1, p=0.0134] (figure e) and ANGPTL6 [LogEC50, Vehicle: -5.7±0.1 vs. ANGPTL6: -6.0±0.1, p=0.0103] (figure c) increased the sensitivity of phenylephrine compared to the control. On the other hand, the hepatokines ANGPTL8, Fetuin-A, Follistatin, GDF-15, Hepassocin, IGF-1, LECT2, Lipocalin-13, SEPP1, and Tsukushi did not change vascular function. These data show that the vascular system senses the presence of hepatokines. Based on these findings, we suggest that hepatokines could be novel therapeutic targets in vascular disease. NHLBI (R00HL151889), NIGMS (1P20GM103641 - Pilot Project), UofSC SOM (Startup funds) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.