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Microcirculatory hyporesponsiveness in lipopolysaccharide-induced inflammation is endothelial cell dependent but calcium independent
Critical Care volume 10, Article number: P95 (2006)
Two hallmarks of sepsis are decreased vascular resistance and hyporeactivity to vasoconstrictor agents in the microcirculation. Whether the impairment in vasoreactivity is caused by defects in the signal transduction pathway inherent to endothelial cells or smooth muscle cells remains unclear.
The aim of this study was to determine whether impaired vasoreactivity during LPS-induced inflammation is associated with altered Ca2+sensitivity of contractile proteins in small mesenteric resistance arteries (SMRA).
LPS (15 mg/kg) or sterile water was injected intraperitoneally into mice. SMRAs were harvested 18 hours after injection. The arterioles (~190–220 μm) were mounted on a pressure myograph, superfused with MOPS buffer at 37°C, and loaded with fura-2. The arteriolar diameter and global intracellular Ca2+ were measured concurrently using light microscopy and a photomultiplier system. Concentration-response curves to phenylephrine (PE) (10-9 to 10-4 M) were conducted. In all experiments, n = 4–6; *P < 0.05 indicates statistical significance.
LPS treatment resulted in hyporesponsiveness to PE as demonstrated with an increase in EC50 (0.7 ± 0.2 μM vs 1.9 ± 1.0 μM*), a decrease in maximal contractile response (Emax 35 ± 6% vs 19 ± 9%*) and a reduction in Ca2+ sensitivity (Fig. 1, left). Removal of the endothelium resulted in a near-normal response to PE in LPS-treated mice (EC50 0.9 ± 0.2 μM vs 1.0 ± 0.6 μM and Emax 43 ± 2% vs 38 ± 5%). Interestingly, Ca2+ sensitivity remained decreased in SMRAs from LPS-treated mice (Fig. 1, right).
In small resistance arteries, LPS-induced inflammation results in endothelial cell dependent hyporesponsiveness to vasoconstrictors in association with, but independent of, a decreased Ca2+ sensitivity within the smooth muscle cells. This suggests that, in the microcirculation, endothelial cells moderate contractility function without affecting calcium sensitivity within the smooth muscle cells.
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Ouellette, Y. Microcirculatory hyporesponsiveness in lipopolysaccharide-induced inflammation is endothelial cell dependent but calcium independent. Crit Care 10, P95 (2006). https://doi.org/10.1186/cc4442
- Smooth Muscle Cell
- Contractile Response
- Calcium Sensitivity
- Vasoconstrictor Agent