Vanderbilt Summer Science Academy

KATP channels sense alterations in shear stress and regulate ductus arteriosus tone

The ductus arteriosus (DA) is a vascular shunt that connects the pulmonary and systematic circulations during fetal life. Lack of DA closure after birth is a significant cardiovascular disorder affecting 1 out of every 500-2000 term infants and 30-40% of the most critically ill neonates. The current treatment options for a patent ductus arteriosus (PDA) are not only limited, but are also associated with several side effects. Therefore, there is a need to explore new treatment options for PDA. The DA experiences a unique pattern of hemodynamic forces and to this point, biomechanical factors have not been studied in the context of regulating DA patency or closure. Ion channels are part of the “druggable genome” and act as mechanosensors in the vasculature. ATP-sensitive K+ (KATP) channels are promising drug targets as they are enriched in the DA and act to regulate DA patency. We hypothesize that KATP channels regulate DA tone by acting as biomechanical sensors. We will test this using human DA smooth muscle cells cultured under various flow conditions. An Ibidi pump system will expose the DA cells to various rates of laminar flow and the expression of several genes including KATP channel genes will be examined using quantitative Real Time RT-PCR. In addition, changes in cell proliferation and cell morphology will be evaluated in static and flow cultures. Overall, the results of this study will give us insight into the role that biomechanical forces play in regulating DA tone and will offer data to support whether KATP channels are a viable drug targets for future treatment of PDA.