Abstract P370: Progranulin Regulates Vascular Function And Blood Pressure Dependent On Ephrin A2 And Sortlin1 Receptors And Nitric Oxide Production.

Abstract

Background: Progranulin (PGRN) is implicated in scar formation, cell proliferation, and anti-inflammation. Although high level of circulating PGRN was previously reported in hypertension, it is still not clear if PGRN can counteract the increases in blood pressure (BP) via modulating vascular tone. We sought to examine the role of PGRN maintaining the vascular tone and BP. Methods: we used male and female global PGRN deficient mice (PGRN-/-) and their counterparts (PGRN+/+) of 10-12-weeks of age to study vascular function and BP by wire myograph and radiotelemetry, respectively. Results: We found that two different mouse models of hypertension (angiotensin II or aldosterone treatments), elevated the levels of circulating PGRN. We also found that male and female PGRN-/- mice display elevated mean arterial pressure (MAP) (mmHg: PGRN+/+: 102.3 ± 3.9 vs PGRN-/-: 112.9 ± 3.7*, *P<0.05) followed by vascular hypercontractility to noradrenaline (NA) [Maximal response (% of 60mM of KCl) male PGRN+/+: 121.9 ± 14.1 PGRN-/-: 152.6 ± 18.8*; female PGRN+/+: 102.6 ± 4.1 and PGRN-/- 131.3 ± 11.4*, *P<0.05) in mesenteric arteries (MA), and increased circulating CCL2, IL-13, and interferon-γ. Whereas replacing PGRN with recombinant PGRN (rPGRN, 20ug/day/7-days) restored the MAP and vascular contractility in PGRN-/-. To explore the mechanisms by which PGRN modulates vascular tone, we treated MA from PGRN+/+, 1-hour prior NA curves, with rPGRN (600ng/mL) and found that PGRN attenuates the vascular contractility, such effect was abolished by blocking Ephrin A2 (EphA2) and Sortlin1 (Sort1) receptors or nitric oxide (NO) synthase (NOS). Next, we freshly isolated endothelial cells (EC) from mesentery of male and female PGRN+/+ mice via magnetic CD31+ microbeads to evaluate any sex difference on EphA2 and Sort1 expressions, which revealed that both receptors are equally expressed in EC from both sexes. In isolated mouse mesenteric EC, rPGRN stimulated NO formation and endothelial NOS activation, which were prevented by blocking EphA2 and Sort1. Conclusion: PGRN adjusts the vascular tone and BP via modulating NO formation and EphA2 and Sort1 receptors activation. Therefore, PGRN might be elevated in hypertension as a tentative to reduce BP by regulating vascular resistance.