The endothelial P2X7 receptor contributes to aortic vascular dysfunction induced by LPS

Sepsis is an organic dysfunction caused by the host deregulated response to infection, in which arterial hypotension is a highly relevant clinical complication. Lipopolysaccharide (LPS) is a key mediator of sepsis. LPS is recognized by the Toll-like receptor (TLR4) and can trigger inflammation through intracellular and extracellular pathways (J Innate Immun. (2021) 13:323). In addition, there is evidence that internalized LPS interacts with the P2X7 receptor (P2X7R). P2X7R is expressed in endothelial cells, which are the lining cells of blood vessels and regulate vascular tone. The objective of this work was to evaluate the effect of the interaction between LPS/TLR4 and P2X7R-mediated signaling in aortic contraction in vitro. Male Wistar rats(2-2.5 months) were euthanized with K/X ip(CEUA 001/24) and the thoracic aorta  was dissected into rings that were fixed in organ chambers, stimulated with 1uM phenylephrine(PHE) and relaxed at the plateau of contraction with 10uM acetylcholine to induce endothelium-dependent relaxation. Rings that relaxed at least 80% or less than 20% were considered to have intact (E+)or absent endothelium(E-), respectively. Subsequently, another contraction was induced with PHE (0.01 to 100 µM) in the absence and presence of the pharmacological treatments: LPS; Benzoyl ATP(BzATP) or the combination LPS and BzATP. The maximal contraction (Emax, %) and EC₅₀ values of PHE were calculated by nonlinear regression analysis. In the E+ group, BzATP did not alter Emax values (84,7± 1,8 and 84,7± 1,8%, n=3), while LPS reduced by the mean Emax value by 15% when compared to the control group (N=4; p<0.005, Student´st test). However, the combination of LPS and BZATP reduced the Emax value of PHE by 30% (N=4; P<0.005)and also increase EC₅₀ values.This difference was absent in E- group. Current data suggest that endothelial P2X7R potentiates vascular hyporreactive induced by LPS/TLR4,and therefore,P2X7R could play a role in sepsis. CAPES, FAPERJ, CNPq.