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Leukocyte-induced endothelial dysfunction in the rabbit basilar artery: modulation by platelet-activating factor
S E Akopov1, R Sercombe, J Seylaz
1Laboratoire de Recherches Cérébrovasculaires, CNRS UA 641, Université Paris VII, France.
Abstract:
We studied the effects of polymorphonuclear leukocytes (PMNLs) activated by N-formyl-methionyl-leucyl-phenylalanine on the endothelium-dependent relaxation of the rabbit basilar artery (BA). In the presence of activated PMNLs the maximal vessel relaxation to acetylcholine (ACh) and bradykinin (endothelium-dependent dilators) was decreased from 62 +/- 7 and 48 +/- 6% to 23 +/- 9 and 19 +/- 7, respectively, (p < 0.05). The endothelium-independent relaxation to nitroprusside was not affected by PMNLs. When PMNLs were activated in the organ chamber in the presence of a low concentration of platelet-activating factor (PAF, 10(-10) mol/l), the depression of ACh- and bradykinin-induced relaxation increased by 27 +/- 9 and 23 +/- 7%, respectively (p < 0.05), though at this concentration PAF alone did not cause PMNLs to induce endothelial dysfunction. In addition, in the presence of PAF, activated PMNLs inhibited endothelium-dependent relaxation at lower cell concentrations and shorter periods of contact with the endothelium. PMNL effects on the endothelium were correlated with the level of cell exocytosis as tested by accumulation of beta-glucuronidase activity. In the presence of PAF, accumulation of this activity increased from 46 +/- 6 to 79 +/- 8 U/ml (p < 0.05). Examination of BA segments by scanning electron microscopy revealed that, after the treatment with activated PMNLs, the endothelium was morphologically preserved, but in the presence of PAF PMNLs caused more apparent microlesions in the endothelial layer. We conclude that small quantities of PAF potentiate the activation of marginated PMNLs. These cells then become more aggressive towards the endothelium, producing significant depression of the endothelium-dependent relaxation.
Insights
Activated polymorphonuclear leukocytes (PMNLs) impair blood vessel relaxation. Platelet-activating factor (PAF) enhances PMNL activation, leading to greater endothelial dysfunction and microlesions in the basilar artery.
Area of Science:
- Vascular biology
- Immunology
- Endothelial function
Background:
- Polymorphonuclear leukocytes (PMNLs) play a role in vascular inflammation.
- Endothelial dysfunction is a key factor in cardiovascular diseases.
- N-formyl-methionyl-leucyl-phenylalanine (fMLP) is a potent activator of PMNLs.
Purpose of the Study:
- To investigate the impact of activated PMNLs on endothelium-dependent relaxation of the rabbit basilar artery (BA).
- To determine the role of platelet-activating factor (PAF) in modulating PMNL-induced endothelial dysfunction.
Main Methods:
- Isolated rabbit basilar artery (BA) segments were used in organ bath studies.
- Endothelium-dependent relaxation was assessed using acetylcholine (ACh) and bradykinin.
- Endothelium-independent relaxation was measured with nitroprusside.
- PMNL activation was induced by fMLP, with or without PAF.
- Beta-glucuronidase activity was measured to assess PMNL exocytosis.
- Scanning electron microscopy (SEM) was used to examine endothelial morphology.
Main Results:
- Activated PMNLs significantly reduced endothelium-dependent relaxation to ACh and bradykinin (p < 0.05).
- PMNLs did not affect endothelium-independent relaxation to nitroprusside.
- Low concentrations of PAF potentiated PMNL-induced inhibition of relaxation.
- PAF enhanced PMNL exocytosis and caused more apparent endothelial microlesions.
- PAF enabled PMNLs to induce dysfunction at lower cell concentrations and shorter contact times.
Conclusions:
- Activated PMNLs significantly impair endothelium-dependent vasodilation.
- Platelet-activating factor (PAF) acts as a potentiator, increasing PMNL aggression towards the endothelium.
- PAF-mediated potentiation of PMNLs leads to exacerbated endothelial dysfunction and morphological damage.