Aims: Nitric oxide synthases (NOSs) are key enzymes regulating vascular function. Previously, we reported that β-adrenergic (β-AR) overstimulation, a common feature of cardiovascular diseases, did not impair endothelium-dependent vasodilation, although it resulted in endothelial NOS (eNOS) uncoupling and reduced NO bioavailability. In addition to NO, neuronal NOS (nNOS) produces H2O2, which contributes to vasodilation. However, there is limited information regarding vascular β-AR signaling and nNOS. In the present study, we assessed the possible role of nNOS-derived H2O2 and caveolins on endothelial vasodilation function following β-AR overstimulation.
Main methods: Male C57BL/6 wild-type and nNOS knockout mice (nNOS-/-) were treated with the β-AR agonist isoproterenol (ISO, 15 mg·kg-1·day-1, s.c.) or vehicle (VHE) for seven days. Relaxation responses of aortic rings were evaluated using wire myograph and H2O2 by Amplex Red.
Key findings: Acetylcholine- or calcium ionophore A23187-induced endothelium-dependent relaxation was similar in aortic rings from VHE and ISO. However, this relaxation was significantly reduced in aortas from ISO compared to VHE when (1) caveolae were disrupted, (2) nNOS was pharmacologically inhibited or genetically suppressed and (3) H2O2 was scavenged. NOS-derived H2O2 production was higher in the aortas of ISO mice than in those of VHE mice. Aortas from ISO-treated mice showed increased expression of caveolin-1, nNOS and catalase, while caveolin-3 expression did not change.
Significance: The results suggest a role of caveolin-1 and the nNOS/H2O2 vasodilatory pathway in endothelium-dependent relaxation following β-AR overstimulation and reinforce the protective role of nNOS in cardiovascular diseases associated with high adrenergic tone.
Keywords: Caveolin-1; Hydrogen peroxide; Neuronal nitric oxide synthase; β-Adrenoceptor.
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