Adipokine, progranulin, attenuates vascular contractility in resistance arteries of male and female mice via sortilin 1 and nitric oxide pathway

Abstract

Introduction: Progranulin (PGRN) is an adipokine, which plays pivotal role in regulating cell growth and inflammation via ephrin type-A2 (EphA2) and/or sortilin1 receptors. In cardiovascular system, PGRN exhibits anti-inflammatory actions, but whether it regulates the vascular tone and whether such effect is a sex-dependent response are still unknown. Aim: We tested the hypothesis that PGRN reduces the vascular adrenergic contractility of resistance arteries dependent on sortilin 1 and nitric oxide (NO), which is not affected by sex. Methods: Mesenteric arteries (MA) from 12-14-week-old male and female C57/BL6J mice were used for studies of vascular function, whereas primary intestinal mesenteric vascular endothelial cells (MEC) were used to explore the molecular mechanisms. Recombinant mouse PGRN was used to treat MA and MEC. Results: PGRN incubation (600ng/mL/1hour) attenuated norepinephrine (NA)-induced contractility in MA from male and female mice at similar magnitude (Maximal response %KCl: Male - Control: 183.4 ± 13.7; PGRN 600 ng/mL: 95.4 ± 16.1*; Female - Control: 164.1 ± 37,1; PGRN 600 ng/mL: 77.8 ± 9.9*, *P<0.05 vs control groups). To study by which receptor PGRN exerts its anti-contractile effects, MA were pre-treated with ALW-ll-41-27(EphA2 antagonist, 0.1uM) or AF38469 (sortilin1 blocker, 4uM). Sortilin1 blockage, but not EphA2, prevented the anti-contractile effect of PGRN in MA. Furthermore, L-NAME [(a non-specific nitric oxide synthase (NOS) inhibitor, 10uM)], blunted the PGRN anti-contractile effects in male and female MA. Fresh mesenteric endothelial cells isolated of mesenteric bed, via CD31 microbeads, revealed that male and female mice present similar levels of sortilin1, EphA2, and endothelial NOS mRNA levels. To dissect the molecular mechanisms, we treated MEC with PGRN and found that PGRN (600ng/mL) increases eNOS phosphorylation at Serine1177 and induces NO production at 30 and 60 minutes, such effects were blunted by sortilin 1 blockage. Conclusion: Our findings indicate that circulating PGRN can assist in maintaining the vascular tone via acting on sortilin1 and leading to NO formation. Our data may have clinical implications on cardiovascular diseases (CVD) associated with changes in endothelial function and vascular tone and place PGRN as a possible pharmacological target. Future investigations are necessary to evaluate the role PGRN as a therapeutic tool in model of CVD. NHLBI-R00 (R00HL14013903), AHA-CDA (CDA857268), Vascular Medicine Institute, the Hemophilia Center of Western Pennsylvania Vitalant, and Children's Hospital of Pittsburgh of the UPMC Health System. 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.