Abstract 5848: Mechanisms of Coronary Arteriolar Myogenic Tone: Role of Down Stream Signaling to EGFR Tyrosine Kinase
Background: Coronary arteriolar (CA) myogenic tone (MT) is critical in local blood flow autoregulation and subsequently in heart perfusion. In previous reports, we showed that epidermal growth factor receptor tyrosine kinase (EGFRtk) is essential in the development of MT. In this study, we determined the intracellular mechanism involved in the MT of CA, focusing on GRB2-SOS, Akt, JAK, and STAT3.
Methods and Results: MT was determined in freshly isolated CA from C57/BL6 mice with and without signaling inhibitors. Pressurized CA under 25 and 75 mmHg were subjected to Western blot analysis to determine signaling phosphorylation. Stimulated cultured smooth muscle cells (SMC) with EGF were used to determine the interaction between signaling. CA MT was significantly reduced under EGFRtk, GRB2-SOS, JAK, and STAT3 inhibition. However, Akt inhibition had no effect on CA MT. Western blot analysis showed increased EGFRtk, STAT3, JAK, and Akt phosphorylation at 75mmHg, which was significantly inhibited under EGFRtk inhibition. Interestingly, immunoprecipitation/ Western blot analysis showed two intracellular complexes (ERK1/2-JAK-STAT3) involved in MT and (AKT-JAK-STAT3) not involved in MT.
Conclusion: These novel findings suggest that the physiological mechanism how EGFRtk dictates CA MT involves ERK1/2-JAK-STAT3 complex with GRB2-SOS, but not Akt, thereby highlighting these signaling events as potential therapeutic targets in cardiovascular disease states associated with compromised myogenic tone.