Endothelium-derived relaxing factors of small resistance arteries in normotensive and hypertensive conditions. EC: endothelial cells, SMC: smooth muscle cells. (A) Small resistance arteries induce vasorelaxation via multiple vasorelaxing pathways including NOS, COX, and EDHF pathways in the normotensive condition. COX in endothelial cells produces PGI 2. PGI 2 can cross the membrane of endothelial cells, and binds IP receptor on the plasma membrane of smooth muscle cells, which induces the activation of the adenylyl cyclase (AC)/cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signal transduction pathway. Activated PKA phosphorylates target proteins, resulting in vasorelaxation. NOS3 produces NO in response to several stimuli such as shear stress, hypoxia, and vasoactive neurotransmitters. NO activates soluble guanylyl cyclase (sGC) in smooth muscle cells. Activated sGC catalyzes the conversion of guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP). cGMP directly and indirectly modulates numerous targets, including protein kinases such as protein kinase G (PKG), resulting in vasorelaxation. Intercellular K + ion, EETs, hydrogen peroxide (H 2 O 2 ), and gap junctions, proposed candidates of EDHF, induce various K + channels activation by complex mechanisms to facilitate hyperpolarization of the underlying smooth muscle cells, which results in vasorelaxation. (B) The NOS-dependent component becomes the primary EDRF pathway in small arteries in the hypertensive condition, in which NOS utilizes both NOS-derived NO/cGMP and NOS-dependent H 2 O 2 to promote vasorelaxation, while other EDRFs are diminished. Endothelium-derived_Relaxing_Factors_of_Small_Resistance_Arteries_in_Hypertension, 2014)
