The endothelium is highly sensitive to acetylcholine and responds to the neurotransmitter by releasing vasodilators that control smooth muscle tone. However, acetylcholine is not expected to reach the endothelium through the vessel wall or via blood. Here, by studying calcium signalling in large areas of the endothelium of intact arteries, we show: (1) the endothelium itself is a source of acetylcholine, (2) acetylcholine release from the endothelium underlies flow-mediated vascular responses; and (3) flow-mediated responses are all but abolished in a rat model of diabetes.
Calcium signalling was studied in large fields of intact endothelia (~150 cells) of carotid and mesenteric arteries from healthy and diabetic rats (Sprague-Dawley, 150–250 g). In both carotid and mesenteric arteries, flow evoked repeatable endothelial calcium signalling. Importantly, flow-mediated calcium responses could be manipulated by modulating cholinergic signalling pathways: the muscarinic receptor blocker, atropine (100 nM), and the acetylcholine hydrolase, acetylcholinesterase (4 U/ml), each abolished flow-induced calcium activity, whilst the acetylcholinesterase inhibitor, neostigmine (10 µM), enhanced calcium activity, and the choline acetyltransferase inhibitor, bromoacetylcholine (50?µM), attenuated responses. Significantly, responses were reduced in diabetic, compared to control, endothelia. Indeed, the number of diabetic endothelial cells responding to flow was 45% of control, and the peak and time-averaged magnitude of calcium signals was reduced to 54% and 12% of control, respectively.
These results identify the endothelium as a source of non-neuronal acetylcholine release and thus demonstrate the reason for the endothelium’s sensitivity to acetylcholine. Significantly, reduced acetylcholine release may underlie the pathophysiology and endothelial dysfunction that occurs in diabetes.
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