Differential Effects of GRB2‐SOS, JNK, STAT and Akt Down Stream Signaling to EGFR Tyrosine Kinase in Mice Coronary Arteriolar Myogenic Tone

Abstract

BackgroundIn a previous report, we showed that epidermal growth factor receptor (EGFR) tyrosine kinase is essential in the development of microvascular myogenic tone (MT). We determined the mechanism of how EGFR tyrosine kinase contributes in the development of mice coronary arteriolar MT focusing on down stream signaling to EGFR: GRB2‐SOS, Akt, JNK and STAT.Methods and resultsFreshly isolated coronary arterioles from C57/BL6 mice were mounted in an arteriograph and stimulated by 25 to 100 mmHg of intraluminal pressure. We performed pressure‐active diameter, passive diameter with and without inhibitors of EGFR tyrosine kinase, GRB2‐SOS, Akt, JNK and STAT. Pressurized coronary arteriolar under 25 and 75 mmHg ± EGFR tyrosine kinase inhibitors were subjected to western blot analysis to determine EGFR tyrosine kinase, GRB2‐SOS, Akt, JNK and STAT phoshorylation.MT was significantly inhibited under EGFR tyrosine kinase inhibition. Similarly, coronary arteriolar MT was significantly reduced under GRB2‐SOS, JNK or STAT inhibitors. However, Akt inhibition had no effect on coronary arteriolar MT. Western blot analysis showed increased EGFR tyrosine kinase, GRB2‐SOS, Akt, JNK and STAT phosphorylation, which were inhibited under EGFR inhibition.ConclusionThese novel findings suggest that EGFR dictates coronary arteriolar myogenic tone involves down stream signaling GRB2‐SOS, JNK and STAT, but not Akt.