FIGURE 6. Proposed mechanism of differential eNOS phosphorylation in endothelium.

Bradykinin activation of the bradykinin receptor 2 (BKR2) causes an increase in eNOS-P in the apical endothelium, leading to significantly decreased leukocyte adhesion via production of anti-inflammatory NO generation. Phenylephrine activation of the α1-AR generates IP₃, which can travel through gap junctions at the MEJ and activate localized IP₃ receptors on the ER. Local ER calcium release contributes to MEJ eNOS-P via activation of MEJ localized PKC, which may occur via Akt. The unique phospholipid composition of the MEJ facilitates this localization of PKC via its lipid cofactors, PS and DAG. Activation of MEJ eNOS with subsequent production of NO leads to increases in SMC cGMP.