Progranulin maintains blood pressure and vascular tone dependent on EphrinA2 and Sortilin1 receptors and eNOS activation

Abstract

AbstractBackgroundThe mechanisms determining vascular tone are still not completely understood, even though it is a significant factor in blood pressure management. Many circulating proteins have a significant impact on controlling vascular tone. Progranulin (PGRN) displays anti-inflammatory effects and has been extensively studied in neurodegenerative illnesses. We investigated whether PGRN sustains the vascular tone that helps regulate blood pressure.MethodsWe used male and female C57BL6/J wild type (PGRN+/+) and B6(Cg)-Grntm1.1Aidi/J (PGRN-/-) to understand the impact of PGRN on vascular contractility and blood pressure.ResultsWe found that male and female PGRN-/- mice display elevated blood pressure followed by hypercontractility to noradrenaline in mesenteric arteries, which are restored by supplementing the mice with recombinant PGRN (rPGRN). Inex vivoexperiments, rPGRN attenuated the vascular contractility to noradrenaline in male and female PGRN+/+ arteries, which was blunted by blocking EphrinA2 or Sortlin1. To understand the mechanisms whereby PGRN evokes anti-contractile effects, we inhibited endothelial factors. L-NAME [nitric oxide (NO) synthase (NOS) inhibitor] prevented the PGRN effects, whereas indomethacin (cyclooxygenases inhibitor) only affected the contractility in arteries incubated with vehicle, indicating the PGRN increases nitric oxide and decreases contractile prostanoids. Finally, rPGRN induced endothelial NOS (eNOS) phosphorylation and NO production in isolated mesenteric endothelial cells.ConclusionCirculating PGRN regulates vascular tone and blood pressure via EphrinA2 and Sortlin1 receptors and eNOS activation. Collectively, our data suggest that deficiency in PGRN is a cardiovascular risk factor and that PGRN might be a new therapeutic avenue to treat high blood pressure.Clinical PerspectiveWhat is new?PGRN displays vascular anti-contractile effects dependent on EphrinA2 and Sortilin1 receptors and nitric oxide formation in male and femaleDeficiency in PGRN triggers high blood pressure and induces vascular dysfunction characterized by hypercontractility to noradrenalinePGRN supplementation restores blood pressure and vascular dysfunction in PGRN-deficient miceWhat are the clinical implications?PGRN deficiency is associated with neurodegenerative diseases including neuronal ceroid lipofuscinosis and frontotemporal dementia (FTD). Our study reveals that a lack of PGRN might be associated with vascular dysfunction and high blood pressureSupplementation with PGRN might be a potential therapeutic route to treat high blood pressure and diseases associated with vascular dysfunctionReduction in PGRN might be a target to screen for higher cardiovascular risk