Mechanisms linking obesity-related disorders to cardiovascular disease, including stroke and other cerebrovascular disorders, are not clearly understood. Apelin is an adipokine that is synthesized by adipocytes and secreted into the circulation. Activation of the apelin/APJ receptor-signaling pathway has vasodilatory effects in important vascular beds (e.g. coronary, pulmonary) and is generally thought to play a protective role in the cardiovascular system; however, the actions of apelin in the cerebral circulation are unknown. The long-term goal is to understand the mechanisms by which apelin regulates vasomotor tone in cerebral arteries. The central hypothesis is that the apelin/APJ receptor axis does not provide a protective vasodilator role in the cerebral circulation, but rather presents a net vasoconstrictor activity in this vascular bed. It is further hypothesized, based on preliminary data produced in the applicant's laboratory, that the apelin-induced vasoconstrictor activity is due to inhibition of large conductance, calcium-activated K (BKCa) channels in cerebral arterial smooth muscle cells. It is proposed that the apelin-mediated inhibition of BKCa channels in cerebral arterial smooth muscle is sufficient to functionally inhibit responsiveness of the arterie to key endogenous vasodilators, including nitric oxide. Inhibition of outward K currents can also be expected to cause depolarization of vascular smooth muscle, resulting in vasoconstriction and/or an increased reactivity to vasoconstrictors. This is significant, as it would predictably increase the risk of cerebral vascular dysfunction in conditions of elevated plasma apelin levels, such as obesity. The following Specific Aims are designed to investigate our hypotheses:
In Aim #1, the potency and efficacy of several apelin peptides in modulating BKCa channel activity in cerebral arterial smooth muscle cells will be quantified using whole cell and single ion channel electrophysiological techniques, and APJ receptor expression and localization will be determined;
In Aim #2, arterial myography will be used to establish the functional consequences of apelin- induced inhibition of BKCa channel activity in cerebral arteries;
In Aim #3, the functional pharmacology of the apelin/APJ system will be compared in cerebral vs coronary arteries, which dilate in response to apelin;
In Aim #4, findings from the rat will be compared with those obtained from isolated human cerebral arteries in order to determine the degree to which data from rat cerebral arteries is translatable. At the completion of the proposed studies, the expectation is that we will have identified the basis for how apelin constricts cerebral arteries, as opposed to its vasodilator effects in peripheral arteries. These results will likely hve a strong positive impact in terms of an increased understanding of the physiologic mechanisms that control the cerebral circulation, as well as provide new targets for therapeutic interventions The knowledge gained from these studies will also fundamentally advance the field of apelin biology, which is expected to have widespread implications for other disorders associated with alterations in apelin signaling.
Cardiovascular disease is a major cause of death and disability in the United States. The proposed research is relevant to public health because the discovery of mechanisms that control blood vessel diameter, and hence blood flow, is ultimately expected to increase our understanding of disorders in which blood vessel function is abnormal or impaired. Thus, the proposed research is relevant to NIH's mission to develop fundamental knowledge that will be useful in developing new approaches to disease prevention and treatment.
| Mughal, Amreen; Sun, Chengwen; O'Rourke, Stephen T (2018) Activation of Large Conductance, Calcium-Activated Potassium Channels by Nitric Oxide Mediates Apelin-Induced Relaxation of Isolated Rat Coronary Arteries. J Pharmacol Exp Ther 366:265-273 |
| Mughal, Amreen; O'Rourke, Stephen T (2018) Vascular effects of apelin: Mechanisms and therapeutic potential. Pharmacol Ther 190:139-147 |
| Mughal, Amreen; Sun, Chengwen; O?Rourke, Stephen T (2018) Apelin Reduces Nitric Oxide-Induced Relaxation of Cerebral Arteries by Inhibiting Activation of Large-Conductance, Calcium-Activated K Channels. J Cardiovasc Pharmacol 71:223-232 |
