Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan, United States.
Transgenic and Genome Editing Facility, Research Technology Support Facility, and Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, Michigan, United States.
Am J Physiol Heart Circ Physiol. 2023 Jul 1;325(1):H172-H186. doi: 10.1152/ajpheart.00239.2023. Epub 2023 Jun 9.
The adipokine chemerin may support blood pressure, evidenced by a fall in mean arterial pressure after whole body antisense oligonucleotide (ASO)-mediated knockdown of chemerin protein in rat models of normal and elevated blood pressure. Although the liver is the greatest contributor of circulating chemerin, liver-specific ASOs that abolished hepatic-derived chemerin did not change blood pressure. Thus, other sites must produce the chemerin that supports blood pressure. We hypothesize that the vasculature is a source of chemerin independent of the liver that supports arterial tone. RNAScope, PCR, Western blot analyses, ASOs, isometric contractility, and radiotelemetry were used in the Dahl salt-sensitive (SS) rat (male and female) on a normal diet. Retinoic acid receptor responder 2 () mRNA was detected in the smooth muscle, adventitia, and perivascular adipose tissue of the thoracic aorta. Chemerin protein was detected immunohistochemically in the endothelium, smooth muscle cells, adventitia, and perivascular adipose tissue. Chemerin colocalized with the vascular smooth muscle marker α-actin and the adipocyte marker perilipin. Importantly, chemerin protein in the thoracic aorta was not reduced when liver-derived chemerin was abolished by a liver-specific ASO against chemerin. Chemerin protein was similarly absent in arteries from a newly created global chemerin knockout in Dahl SS rats. Inhibition of the receptor Chemerin1 by the receptor antagonist CCX832 resulted in the loss of vascular tone that supports potential contributions of chemerin by both perivascular adipose tissue and the media. These data suggest that vessel-derived chemerin may support vascular tone locally through constitutive activation of Chemerin1. This posits chemerin as a potential therapeutic target in blood pressure regulation. Vascular tunicas synthesizing chemerin is a new finding. Vascular chemerin is independent of hepatic-derived chemerin. Vasculature from both males and females have resident chemerin. Chemerin1 receptor activity supports vascular tone.
脂肪因子趋化素可能有助于维持血压，这一点在正常和高血压大鼠模型中得到了证实，即在全身反义寡核苷酸（ASO）介导的趋化蛋白敲低后，平均动脉压下降。虽然肝脏是循环趋化素的最大贡献者，但消除肝源性趋化素的肝特异性 ASO 并未改变血压。因此，其他部位必须产生支持血压的趋化素。我们假设血管是一种独立于肝脏的趋化素来源，它支持动脉张力。在正常饮食的 Dahl 盐敏感（SS）大鼠（雄性和雌性）中使用了 RNAScope、PCR、Western blot 分析、ASO、等长收缩性和无线电遥测技术。在胸主动脉的平滑肌、外膜和血管周围脂肪组织中检测到维甲酸受体应答 2（）mRNA。免疫组织化学检测到趋化素蛋白在内皮细胞、平滑肌细胞、外膜和血管周围脂肪组织中表达。趋化素与血管平滑肌标志物α-肌动蛋白和脂肪细胞标志物 perilipin 共定位。重要的是，当通过针对趋化素的肝特异性 ASO 消除肝源性趋化素时，胸主动脉中的趋化素蛋白并未减少。在 Dahl SS 大鼠中创建的新的全局趋化素敲除的动脉中，也同样缺乏趋化素蛋白。趋化素受体 Chemerin1 的抑制剂 CCX832 导致支持血管张力的丧失，这可能是血管周围脂肪组织和中膜趋化素的潜在贡献。这些数据表明，血管源性趋化素可能通过血管周围脂肪组织和中膜的组成性激活 Chemerin1 来支持局部血管张力。这表明趋化素可能是血压调节的潜在治疗靶点。血管外膜合成趋化素是一个新的发现。血管趋化素独立于肝源性趋化素。来自男性和女性的血管都有常驻趋化素。Chemerin1 受体活性支持血管张力。
