Vascular reactivity stimulated by TMA and TMAO: Are perivascular adipose tissue and endothelium involved?

Nov 16, 2020Pharmacological research

Blood vessel response to TMA and TMAO: Role of surrounding fat and inner lining

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Abstract

TMA and TMAO caused concentration-dependent arterial contraction, with TMA inducing a contraction of 141.5 ± 16% of maximum phenylephrine contraction at 0.2 M.

TMAO-induced contraction was significantly reduced in the presence of endothelium, indicating a protective role of the endothelium.
FMO3 enzyme was identified in the aortic perivascular adipose tissue.
The FMO3 inhibitor methimazole did not alter contraction caused by TMA in aorta with perivascular adipose tissue.
Nifedipine, a calcium channel blocker, reduced TMA-induced contraction by approximately 50%, suggesting calcium channels are involved.
High concentrations of TMA and TMAO are needed to elicit arterial contraction, but their effects may be physiologically relevant.

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Trimethylamine (TMA), formed by intestinal microbiota, and its Flavin-Monooxygenase 3 (FMO3) product Trimethylamine-N-Oxide (TMAO), are potential modulators of host cardiometabolic phenotypes. High circulating levels of TMAO are associated with increased risk for cardiovascular diseases. We hypothesized that TMA/TMAO could directly change the vascular tone. Perivascular adipose tissue (PVAT) helps to regulate vascular homeostasis and may also possess FMO3. Thoracic aorta with(+) or without(-) PVAT, also + or - the endothelium (E), of male Sprague Dawley rats were isolated for measurement of isometric tone in response to TMA/TMAO (1nM-0.5 M). Immunohistochemistry (IHC) studies were done to identify the presence of FMO3. TMA and TMAO elicited concentration-dependent arterial contraction. However, at a maximally achievable concentration (0.2 M), contraction stimulated by TMA was of a greater magnitude (141.5 ± 16% of maximum phenylephrine contraction) than that elicited by TMAO (19.1 ± 4.03%) with PVAT and endothelium intact. When PVAT was preserved, TMAO-induced contraction was extensively reduced the presence (19.1 ± 4.03%) versus absence of E (147.2 ± 20.5%), indicating that the endothelium plays a protective role against TMAO-induced contraction. FMO3 enzyme was present in aortic PVAT, but the FMO3 inhibitor methimazole did not affect contraction stimulated by TMA in aorta + PVAT. However, the l-type calcium channel blocker nifedipine reduced TMA-induced contraction by ∼50% compared to the vehicle. Though a high concentration of these compounds was needed to achieve contraction, the findings that TMA-induced contraction was independent of PVAT and E and mediated by nifedipine-sensitive calcium channels suggest metabolite-induced contraction may be physiologically important.

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Vascular reactivity stimulated by TMA and TMAO: Are perivascular adipose tissue and endothelium involved?

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