Formyl peptide receptor induces vascular unresponsiveness to noradrenaline via disruption of actin polymerization

Vascular hyporeactivity to adrenergic stimulation is a significant independent prognostic factor of mortality in sepsis. Loss of vascular tone occurs through complex, multifactorial mechanisms that have not been fully elucidated. Formyl peptide receptor (FPR) is an innate immune system receptor that is activated by bacterial and mitochondrial fragments called N‐formyl peptides. Previously, we have observed that FPR stimulation with both mitochondrial and bacterial N‐formyl peptides leads to reduced noradrenaline‐induced contraction in resistance arteries and hypotension. Therefore, we first hypothesized that the absence of FPR would increase vascular noradrenaline contraction. To test this hypothesis we used male, 8–10 week old wild‐type (WT; C57BL/6) or FPR‐1 knockout (KO) mice to measure vascular function in mesenteric resistance arteries (MRA, diameter ~180 μm) and aorta. Surprisingly our hypothesis was refuted, since the absence of global FPR induced similar hyporesponsiveness to noradrenaline‐induced contraction (10 −10 –10 −4 M) in all arterial beds (E max : MRA: WT: 10.6 ± 0.4 vs. FPR‐1 KO: 8.3 ± 0.5 mN, p<0.05; Aorta: WT: 5.4 ± 1.2 vs. FPR‐1 KO: 0.6 ± 0.2 mN, p<0.05). This result suggested that the absence of FPR mimics its desensitization which leads to vascular unresponsiveness to noradrenaline. Loss of vascular tone and desensitization to adrenergic agents could be a result of cytoskeleton disruption. In fact, it is known that FPR activation by N‐formyl peptides leads to changes in cytoskeleton‐regulating proteins in leukocytes. Consequently, we hypothesized that the mechanistic pathway that leads to vascular unresponsiveness following FPR desensitization and/or absence is due to a disruption in actin polymerization. To assess if FPR‐1 interferes with actin polymerization, some arteries from WT or FPR‐KO mice were incubated with cytochalasin B (CYTO B, 10 −6 M) (inhibits both the rate of actin polymerization and the interaction of actin filaments in solution) or jasplakinolide (JASP, 10 −7 M) (promotes actin‐stabilizing and polymerization). JASP increased noradrenaline‐induced contraction only in arteries from FPR‐1 KO. On the other hand, CYTO abolished noradrenaline‐induced‐contraction in arteries from both strains of mice, suggesting that actin polymerization is crucial for noradrenaline‐induced contraction. Overall, these data suggest that FPR hyperstimulation, which leads to desensitization, and absence induces vascular unresponsiveness in conductance and resistance arteries via disruption of actin polymerization. Given that patients with sepsis have high levels of N‐formyl peptides (bacterial and mitochondrial), FPR desensitization can occur in these patients due to its hyperstimulation. Since noradrenaline administration is known to be ineffective at reversing vascular collapse and hypotension in septic patients, perhaps reconstituting FPR sensitization and/or actin polymerization could be putative treatment targets. Support or Funding Information Research Support: National Institutes of Health (NIH: 1K99GM118885‐01)