Endothelial epidermal growth factor receptor is of minor importance for vascular and renal function and obesity-induced dysfunction in mice

Abstract

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.