Polarized localization of phosphatidylserine in endothelium regulates Kir2.1

In the resistance artery endothelium, we show phosphatidylserine (PS) localizes to a specific subpopulation of myoendothelial junctions (MEJs), signaling microdomains that regulate vasodilation. In silico data has implied PS may compete with PIP 2 binding on Kir2.1, a channel involved in vasodilatory signaling. We found 83.33% of Kir2.1-MEJs also contained PS, possibly indicating an interaction where PS regulates Kir2.1. Electrophysiology experiments on HEK cells demonstrate PS blocks PIP 2 activation of Kir2.1, and addition of exogenous PS blocks PIP 2 -mediated Kir2.1 vasodilation in resistance arteries. Using a mouse model lacking canonical MEJs in resistance arteries ( Eln fl/fl /Cdh5-Cre), PS localization in endothelium was disrupted and PIP 2 activation of Kir2.1 was significantly increased. Taken together, our data suggests PS enrichment to MEJs inhibits PIP 2 -mediated activation of Kir2.1 to tightly regulate changes in arterial diameter, and demonstrates the intracellular lipid localization within endothelium is an important determinant of vascular function.