Electro‐metabolic signaling in heart: how local blood flow is regulated

Abstract

How local blood flow is controlled in heart has proved a mystery after decades of extensive investigation by many research groups. Multiple metabolic products and factors have been suggested to affect coronary blood flow and to contribute its regulation. Nevertheless, how this blood flow is regulated and shown to be responsive to metabolic need remains unclear. Our new observations provided compelling evidence for electro‐metabolic signaling (Zhao et al. PNAS 2020) that originates in ventricular myocytes and is conducted to capillary endothelial cells and then to contractile smooth muscle cells and pericytes. This hypothesis posits that the metabolic sensors are the contractile myocytes themselves and the information distribution system is an electrical network composed of the same capillaries that distribute the oxygen‐rich blood. The “valves” that open to permit more blood to flow to the needy myocytes or close to slow the flow are contractile smooth muscle cells on the end‐arterioles and also the contractile pericytes attached to the capillary endothelial cells and end‐arterioles. Each of these critical elements communicate with the other electrically in a functioning EMS communication system because gap junctions (or the equivalent) connect them. As cardiac myocytes carry out pressure‐volume work, they consume ATP and produce elevated ADP. This leads to a decline in [ATP] and an increase in [ADP], actions that lead to the opening of KATP channels which are hugely abundant in the cardiac myocytes and which drive EMS. This produces a time‐averaged hyperpolarization of the cardiac action potential (AP) which produces a low‐pass filtered hyperpolarization in the neighboring EMS network. To confirm and extend our hypothesis and observations, additional studies have been conducted on perfused and pressurized mouse cardiac papillary muscle preparations to investigate how signals from cardiac myocytes are sent through the neighboring capillaries to the contractile elements. Specifically, gap junction permeable dye (lucifer yellow, LY), was used to trace the intercellular conduction pathway and cdh5‐GCaMP8 mice were used to evaluate the effect of myocyte voltage on capillary endothelial cells function. Optogenetic experiments with channel‐rhodopsin was also used to evaluate the intercellular signals from capillary endothelial cells to pericytes, vascular smooth muscle cells and cardiac myocytes. Our results show that when LY was injected into the cardiac myocytes it was also observed in the neighboring capillaries. Hyperpolarization of cardiac myocyte was also shown to hyperpolarize capillary endothelial cells. These investigations provide stunning and compelling support for electro‐metabolic signaling and lay the foundation for advanced investigations of its dynamic role in health and disease.