Regulation of Vascular Tone in Cerebral and Coronary Arteries by Apelin/APJ Receptor Mechanisms

Abstract

The peptide, apelin, is expressed in fat cells, endothelial cells, and CNS neurons. Increasing evidence (e.g. inotropic and vasomotor effects) supports a role for apelin in the regulation of the cardiovascular system. This research aimed to understand vascular effects of apelin and bridge gaps in the knowledge about apelin-induced effects on different vascular beds i.e. cerebral and coronary arteries. My first objective was to assess apelin-induced vascular effects in cerebral arteries. Based on current data, one could conclude that apelin by itself has no effects on vasomotor tone of cerebral arteries, but it does impair nitric oxide dependent relaxations of cerebral arteries, possibly by inhibiting functions of large conductance calcium activated potassium (BKCa) channels. Apelin increases coronary blood flow; however, the involved mechanism(s) has not yet been elucidated. Hence, my next aim was to determine the mechanism(s) involved in apelin-induced vascular effects. The results suggest that apelin causes endothelium APJ receptor dependent relaxation of coronary arteries, which is possibly mediated by nitric oxide dependent direct activation of BKCa channels. Interestingly, my results also suggest that pathways involved in apelin-induced coronary arteries relaxation are markedly different from another endothelium dependent vasodilator, acetylcholine. This research is the first to report that nitric oxide, generated in response to different stimuli, can likely activate more than one signaling pathways in coronary arteries. In my final aim, I determined effects of apelin on smooth muscle BKCa channel functions in coronary arteries. My data suggest that functionally active apelin-APJ signaling has no inhibitory effects on BKCa channel functions and does not inhibit nitric oxide-induced relaxations of coronary arteries. Possible reasons for difference in apelin response between cerebral and coronary arteries could be associated with differences in activation of G-proteins and PI3K signaling pathways between these two vascular beds. Altogether, this research provides an improved understanding about apelin-induced vascular effects in cerebral and coronary arteries, and highlights some key mechanistic differences in apelin-induced vascular effects between these two blood vessels. Moreover, this knowledge may have important therapeutic implications in future design and development of apelin analogs for treatment of cardiovascular diseases.