Knock-out of vascular smooth muscle epidermal growth factor receptor prevents obesity-induced vascular dysfunction and renal damage in vivo

Abstract

Aim: Obesity causes diabetes type 2 (DMT2) leading to vascular dysfunction and finally renal end-organ damage. Vascular smooth muscle (VSM) EGF receptor (EGFR) modulates vascular wall homeostasis in part via serum response factor (SRF), a major regulator of VSM differentiation and a sensor for glucose. We investigated the role of VSM-EGFR during obesityinduced renovascular dysfunction and the underlying mechanisms related to EGFRhyperglycemia crosstalk. Methods: The role of VSM-EGFR during high fat diet (HFD)-induced DMT2 was investigated in a mouse model with inducible, VSM-specific EGFR knock out (KO). Various structural and functional parameters as well as transcriptome changes in vivo and ex vivo were assessed. The impact of hyperglycemia on EGFR-induced signaling and SRF transcriptional activity and the underlying mechanisms were investigated at the cellular level. Results: We show that VSM-EGFR mediates obesity/DMT2-induced vascular dysfunction, remodeling and transcriptome dysregulation preceding renal damage and identify an EGFRglucose synergism in terms of SRF activation, matrix dysregulation and mitochondrial function. EGFR-deletion protects the animals from HFD-induced endothelial dysfunction, creatininemia and albuminuria. Furthermore, we show that HFD led to marked changes of the aortic transcriptome in WT but not in KO animals, indicative of EGFR-dependent SRF activation, matrix dysregulation and mitochondrial dysfunction, the latter confirmed at the cellular level. Studies at the cellular level revealed that high glucose potentiated EGFR/ErbB2-induced stimulation of SRF activity, enhancing the graded signaling responses to EGF, via the EGFR/ErbB2-ROCK-actin-MRTF-pathway and promoted mitochondrial dysfunction. Conclusions: VSM-EGFR contributes to HFD-induced vascular and subsequent renal alterations as the result of a potentiated EGFR/ErbB2-ROCK-MRTF-SRF signaling axis and mitochondrial dysfunction. VSM-EGFR may be a therapeutic target in cases of DMT2-induced renovascular disease.