Department of Pediatrics University of Pittsburgh Pittsburgh PA USA.
Center for Pediatrics Research in Obesity and Metabolism (CPROM) Pittsburgh PA USA.
J Am Heart Assoc. 2023 Aug 15;12(16):e030353. doi: 10.1161/JAHA.123.030353. Epub 2023 Aug 10.
Background The 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 displays anti-inflammatory effects and has been extensively studied in neurodegenerative illnesses. We investigated whether progranulin sustains the vascular tone that helps regulate blood pressure. Methods and Results We used male and female C57BL6/J wild type (progranulin) and B6(Cg)-Grn/J (progranulin) to understand the impact of progranulin on vascular contractility and blood pressure. We found that progranulin mice display elevated blood pressure followed by hypercontractility to noradrenaline in mesenteric arteries, which is restored by supplementing the mice with recombinant progranulin. In ex vivo experiments, recombinant progranulin attenuated the vascular contractility to noradrenaline in male and female progranulin arteries, which was blunted by blocking EphrinA2 or Sortilin1. To understand the mechanisms whereby progranulin evokes anticontractile effects, we inhibited endothelial factors. N(gamma)-nitro-L-arginine methyl ester (nitric oxide synthase inhibitor) prevented the progranulin effects, whereas indomethacin (cyclooxygenase inhibitor) affected only the contractility in arteries incubated with vehicle, indicating that progranulin increases nitric oxide and decreases contractile prostanoids. Finally, recombinant progranulin induced endothelial nitric oxide synthase phosphorylation and nitric oxide production in isolated mesenteric endothelial cells. Conclusions Circulating progranulin regulates vascular tone and blood pressure via EphrinA2 and Sortilin1 receptors and endothelial nitric oxide synthase activation. Collectively, our data suggest that deficiency in progranulin is a cardiovascular risk factor and that progranulin might be a new therapeutic avenue to treat high blood pressure.
尽管血管张力是血压管理的重要因素，但决定其的机制仍不完全清楚。许多循环蛋白对控制血管张力有重大影响。颗粒蛋白前体显示出抗炎作用，并在神经退行性疾病中得到了广泛研究。我们研究了颗粒蛋白前体是否维持有助于调节血压的血管张力。
我们使用雄性和雌性 C57BL6/J 野生型（颗粒蛋白前体）和 B6(Cg)-Grn/J（颗粒蛋白前体）来了解颗粒蛋白前体对血管收缩性和血压的影响。我们发现，颗粒蛋白前体小鼠表现出血压升高，随后对去甲肾上腺素的血管收缩性增强，这在给小鼠补充重组颗粒蛋白前体后得到恢复。在离体实验中，重组颗粒蛋白前体减弱了雄性和雌性颗粒蛋白前体血管对去甲肾上腺素的血管收缩性，而 EphrinA2 或 Sortilin1 阻断则减弱了这种作用。为了了解颗粒蛋白前体引起抗收缩作用的机制，我们抑制了内皮因子。N(gamma)-硝基-L-精氨酸甲酯（一氧化氮合酶抑制剂）阻止了颗粒蛋白前体的作用，而吲哚美辛（环氧化酶抑制剂）仅影响用载体孵育的动脉的收缩性，表明颗粒蛋白前体增加了一氧化氮并减少了收缩性前列腺素。最后，重组颗粒蛋白前体诱导了分离的肠系膜内皮细胞中内皮型一氧化氮合酶磷酸化和一氧化氮产生。
循环颗粒蛋白前体通过 EphrinA2 和 Sortilin1 受体和内皮型一氧化氮合酶激活来调节血管张力和血压。总的来说，我们的数据表明，颗粒蛋白前体缺乏是心血管风险因素，而颗粒蛋白前体可能是治疗高血压的新治疗途径。
