Mechanism of endothelium-dependent dilation. Upon agonist stimulation, endothelial nitric oxide synthase (eNOS) activity increases to generate nitric oxide (NO). NO diffuses across the internal elastic lamina (IEL) to relax the underlying smooth muscle cells (SMC). Arachidonic acid (AA) metabolism by cyclooxygenase (COX) enzymes to produce prostaglandin H2 (PGH2). In turn, this is converted to prostacyclin (PGI2) by prostacyclin synthase (PS), and mediates relaxation through the prostacyclin receptor (IP). Endothelial cell plasma membrane hyperpolarization generated by K+ efflux (ΔEm) spreads through myoendothelial gap junctions (MEGJ) to promote endothelium-dependent hyperpolarization (EDH) and relaxation. Several other factors, collectively termed as endothelium-derived hyperpolarizing factor (EDHF), hyperpolarizes smooth muscle cells to evoke relaxation.