Fast, transient relaxation of rat pulmonary artery by angiotensin II via AT1R‐eNOS signaling pathways

Abstract

Angiotensin II (AngII) is conventionally known as a vasoconstrictive agonist in the large conduit arteries. However, our preliminary study showed that the application of AngII induces only a transient, weak contraction in pulmonary arteries (PAs) followed by persistent desensitization. We have previously reported eNOS expression in pulmonary smooth muscle cells (PASMCs). Here we hypothesized that the concomitant activation of the myogenic eNOS by AngII might limit the contractile responses of PA. Myograph study (isometric contraction of vessel rings) of the rat PAs showed biphasic dose‐response to AngII with peak response at 1 μM. When pre‐treated with L‐NAME (NOS inhibitor) or ODQ (guanylate cyclase inhibitor), the transient AngII‐contraction became augmented and sustained. The AngII‐contraction was abolished by losartan (AT1 receptor antagonist), while neither PD123319 (AT2 receptor antagonist) nor A779 (Mas receptor antagonist) affected the AngII‐contraction. In human PASMCs, eNOS expression was confirmed, and the pro‐activating phosphorylation of Ser 473 in Akt and Ser 1177 in eNOS by AngII treatment was consistently observed by immunoblot. Also, the membrane expression of AT1R was sensitively shifted to the cytosol by AngII. Consistent with the AT1R internalization, the second AngII hardly induced any contractile response in PAs. Interestingly, the desensitization was also significantly removed by the treatment of L‐NAME, immediately after the washout of first AngII application, suggesting the involvement of eNOS signaling pathway in the control of AT1R recycling. Taken together, we proposed that the auto‐inhibitory role of the muscular eNOS in PAs play physiological roles of active relaxation under various vasoconstrictive conditions, preventing excessive contractile response of the low‐pressure pulmonary circulation.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.