Julius-Bernstein-Institute of Physiology, Martin Luther University Halle-Wittenberg, Magdeburger Strasse 6, 06112, Halle (Saale), Germany.
Institute of Pathology, Martin Luther University Halle-Wittenberg, Halle, Germany.
Sci Rep. 2021 Mar 31;11(1):7269. doi: 10.1038/s41598-021-86587-3.
Vascular EGF receptors (EGFR) influence function and structure of arterial vessels. In genetic mouse models we described the role of vascular smooth muscle (VSMC) EGFR for proper physiological function and structure as well as for pathophysiological alterations by obesity or angiotensin II. As the importance of endothelial (EC) EGFR in vivo is unknown, we analyzed the impact of EC-EGFR knockout in a conditional mouse model on vascular and renal function under control condition as well as in obesity and in comparison to VSMC-KO. Heart and lung weight, blood pressure and aortic transcriptome (determined by RNA-seq) were not affected by EC-EGFR-KO. Aortic reactivity to α1-adrenergic stimulation was not affected by EC-EGFR-KO contrary to VSMC-EGFR-KO. Endothelial-induced relaxation was reduced in abdominal aorta of EC-EGFR-KO animals, whereas it was enhanced in VSMC-EGFR-KO animals. Mesenteric arteries of EC-EGFR-KO animals showed enhanced sensitivity to α1-adrenergic stimulation, whereas endothelial-induced relaxation and vessel morphology were not affected. Renal weight, histomorphology, function (albumin excretion, serum creatinine, fractional water excretion) or transcriptome were not affected by EC-EGFR-KO, likewise in VSMC-EGFR-KO. High fat diet (HFD) over 18 weeks induced arterial wall thickening, renal weight increase, creatininemia, renal and aortic transcriptome alterations with a similar pattern in EC-EGFR-WT and EC-EGFR-KO animals by contrast to the previously reported impact of VSMC-EGFR-KO. HFD induced endothelial dysfunction in abdominal aortae of EC-EGFR-WT, which was not additive to the EC-EGFR-KO-induced endothelial dysfunction. As shown before, VSMC-EGFR-KO prevented HFD-induced endothelial dysfunction. HFD-induced albuminuria was less pronounced in EC-EGFR-KO animals and abrogated in VSMC-EGFR-KO animals. Our results indicate that EC-EGFR, in comparison to VSMC-EGFR, is of minor and opposite importance for basal renovascular function as well as for high fat diet-induced vascular remodeling and renal end organ damage.
血管表皮生长因子受体（EGFR）影响动脉血管的功能和结构。在遗传小鼠模型中，我们描述了血管平滑肌（VSMC）EGFR 在正常生理功能和结构以及肥胖或血管紧张素 II 引起的病理生理改变中的作用。由于内皮（EC）EGFR 在体内的重要性尚不清楚，我们在条件性小鼠模型中分析了 EC-EGFR 敲除对血管和肾功能的影响，包括在对照条件下、肥胖情况下以及与 VSMC-KO 的比较。心、肺重量、血压和主动脉转录组（通过 RNA-seq 确定）不受 EC-EGFR-KO 的影响。与 VSMC-EGFR-KO 相反，α1-肾上腺素能刺激引起的主动脉反应不受 EC-EGFR-KO 的影响。EC-EGFR-KO 动物的腹主动脉内皮诱导性松弛减弱，而 VSMC-EGFR-KO 动物的内皮诱导性松弛增强。EC-EGFR-KO 动物肠系膜动脉对α1-肾上腺素能刺激的敏感性增强，而内皮诱导性松弛和血管形态不受影响。EC-EGFR-KO 或 VSMC-EGFR-KO 动物的肾脏重量、组织形态学、功能（白蛋白排泄、血清肌酐、水分排泄分数）或转录组不受影响。18 周高脂肪饮食（HFD）导致动脉壁增厚、肾脏重量增加、血肌酐升高、肾脏和主动脉转录组改变，其模式与之前报道的 VSMC-EGFR-KO 影响相似。HFD 诱导 EC-EGFR-WT 腹主动脉内皮功能障碍，与之前报道的 VSMC-EGFR-KO 诱导的内皮功能障碍没有叠加。HFD 诱导的 EC-EGFR-WT 腹主动脉内皮功能障碍，与之前报道的 VSMC-EGFR-KO 诱导的内皮功能障碍没有叠加。与之前报道的 VSMC-EGFR-KO 诱导的内皮功能障碍没有叠加。HFD 诱导的白蛋白尿在 EC-EGFR-KO 动物中不明显，并在 VSMC-EGFR-KO 动物中被消除。我们的结果表明，与 VSMC-EGFR 相比，EC-EGFR 对基础肾血管功能以及高脂肪饮食诱导的血管重塑和肾脏终末器官损伤的重要性较小，作用相反。
