Effects of Acetate on Mesenteric Lymphatic Pump Function
Authors: Singh Reetu , Stewart Randolph H. , Laine Glen A. , Dongaonkar Ranjeet M. 
Published: May 2022

Pump function of mesenteric lymphatic vessels (MLVs) is essential for active transport of intestinal lymph and lipids from the gut to the venous circulation. MLV pump function is also critical for transport of immune cells in the GI tract, which account for almost 70% of the body’s immune cells. Short‐chain fatty acids (SCFAs)—the metabolites of the intestinal microbiota—are absorbed rapidly across the intestinal epithelial barrier and their concentration reaches 1‐100 mM in the intestinal tissues. There is a growing interest in the effects SCFAs on blood vessels. Blood vessel studies using acetate, the most abundant SCFA in peripheral circulation, reported that vasodilation induced by acetate mediates the blood pressure lowering effects of acetate. Furthermore, nitric oxide (NO) pathway was identified to mediate the acetate‐induced vasodilation. MLVs are exposed to significantly higher SCFA concentrations (as high as those in the intestinal tissues) in the undiluted lymph compared to the blood vessels. However, the effects of SCFAs on lymphatic vessel function have yet to be investigated thoroughly. Therefore, the purpose of the present study was to evaluate our hypothesis that acetate induces lymphatic dilation and decreases lymphatic pump function.

MLVs were isolated from male Sprague Dawley rats and cannulated and perfused with warm APSS. Transmural pressure was set to 3 cmH2O and MLVs were allowed to equilibrate. In spontaneously contracting vessels, changes in pump function in response to cumulative concentrations of acetate (10‐8 to 10‐2M) were determined. In separate MLVs, pump function at three transmural pressures (3, 5 and 7 cmH2O; selected randomly) was evaluated before and after incubating the MLVs with acetate (10 mM). Additionally, in another set of MLVs, lymphatic pump function at three transmural pressures (3, 5 and 7 cmH2O; selected randomly) was evaluated before and after incubating the MLVs with N(ω)‐nitro‐L‐arginine methyl ester (L‐NAME; 100 µM) and again after incubating the MLVs with L‐NAME (100 µM) + acetate (10 mM).

The dose‐response study revealed that acetate led to decrease in lymphatic contraction frequency and calculated active lymph flow in a dose‐dependent manner. IC50 of the dose‐response curve was 1mM and lymphatic pumping was completely abolished at 50 mM concentration. Lymphatic contraction frequency and calculated active lymph flow were significantly decreased at all transmural pressures. Lymphatic stroke volume normalized to passive volume and diastolic tone were not significantly altered by acetate. Blockade of the NO pathway with L‐NAME did not restore the acetate‐induced decrease in lymphatic contraction frequency at all transmural pressures.

Consistent with the effects of acetate on the blood vessels, acetate decreased lymphatic pump function in a dose‐dependent manner. However, the findings suggest that the NO pathway, reported to mediate blood vessel responses to acetate, does not mediate lymphatic responses to acetate. Two different pathways mediating acetate‐induced vasodilation in blood and lymphatic vessels may enable regulation of blood or lymphatic vessel function independently.