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Circulating microparticles from Crohn's disease patients cause endothelial and vascular dysfunctions.

Leonetti D, Reimund JM, Tesse A, Viennot S, Martinez MC, Bretagne AL, Andriantsitohaina R - PLoS ONE (2013)

Bottom Line: Circulating MP levels did not differ between HS and inactive CD patients except for an increase in leukocyte-derived MPs in CD.A significant correlation was found between total levels of MPs, those from platelets and endothelial cells, and the Harvey-Bradshaw clinical activity index.CDMPs induced vascular hypo-reactivity in aorta that was prevented by a nitric oxide (NO)-synthase inhibitor, and was associated with a subtle alteration of the balance between NO, reactive oxygen species and the release of COX metabolites.

View Article: PubMed Central - PubMed

Affiliation: LUNAM Université, Angers, France ; INSERM, U1063, Angers, France.

ABSTRACT

Background: Microparticles (MPs) are small vesicles released during cell activation or apoptosis. They are involved in coagulation, inflammation and vascular dysfunction in several diseases. We characterized circulating MPs from Crohn's Disease (CD) patients and evaluated their effects on endothelial function and vascular reactivity after in vivo injection into mice.

Methods: Circulating MPs and their cellular origins were examined by flow cytometry from blood samples from healthy subjects (HS) and inactive or active CD patients. MPs were intravenously injected into mice. After 24 hours, endothelial function and vascular reactivity were assessed.

Results: Circulating MP levels did not differ between HS and inactive CD patients except for an increase in leukocyte-derived MPs in CD. Active CD patients compared to HS displayed increased total circulating MPs, pro-coagulant MPs and those from platelets, endothelium, erythrocytes, leukocytes, activated leukocytes and activated platelets. A significant correlation was found between total levels of MPs, those from platelets and endothelial cells, and the Harvey-Bradshaw clinical activity index. MPs from CD, but not from HS, impaired endothelium-dependent relaxation in mice aorta and flow-induced dilation in mice small mesenteric arteries, MPs from inactive CD patients being more effective than those from active patients. CDMPs induced vascular hypo-reactivity in aorta that was prevented by a nitric oxide (NO)-synthase inhibitor, and was associated with a subtle alteration of the balance between NO, reactive oxygen species and the release of COX metabolites.

Conclusions: We provide evidence that MPs from CD patients significantly alter endothelial and vascular function and therefore, may play a role in CD pathophysiology, at least by contributing to uncontrolled vascular-dependent intestinal damage.

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Related in: MedlinePlus

Microparticles (MPs) from active CD patients induce nitric oxide (NO) overproduction in mouse aorta.Concentration-effect curves of 5-HT in the presence and in the absence of L-NA in aortic rings isolated from mice injected in vivo with vehicle (controls (CTL)) and MPs from HS (HSMPs) (A) and with MPs from active CD patients (active CDMPs) (B). Contraction are expressed in mN/mm. Results are given as mean ± SEM (n = 7–8). NO production (C) assessed by the amplitude of NO-Fe(DETC)2 complex signal and superoxide anion (O2−) production (D) assessed by the amplitude of O2–CMH complex signal in unit/weight in aorta from mice injected in vivo with vehicle (CTL), HSMPs and active CDMPs. Results are given as mean ± SEM (n = 5–7). **p<0.01; ***p<0.001 vs CTL.
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pone-0073088-g006: Microparticles (MPs) from active CD patients induce nitric oxide (NO) overproduction in mouse aorta.Concentration-effect curves of 5-HT in the presence and in the absence of L-NA in aortic rings isolated from mice injected in vivo with vehicle (controls (CTL)) and MPs from HS (HSMPs) (A) and with MPs from active CD patients (active CDMPs) (B). Contraction are expressed in mN/mm. Results are given as mean ± SEM (n = 7–8). NO production (C) assessed by the amplitude of NO-Fe(DETC)2 complex signal and superoxide anion (O2−) production (D) assessed by the amplitude of O2–CMH complex signal in unit/weight in aorta from mice injected in vivo with vehicle (CTL), HSMPs and active CDMPs. Results are given as mean ± SEM (n = 5–7). **p<0.01; ***p<0.001 vs CTL.

Mentions: To investigate the role of NO, the effect of the NO-synthase inhibitor, L-NA, was studied on the response to 5-HT. Interestingly, we found that inhibition of the NO pathway did not affect response to 5-HT in vessels from HSMPs (Figure 6A) but completely prevented the vascular hypo-reactivity induced by active CDMPs (Figure 6B). Direct in situ measurements of NO production were performed by EPR spectroscopy using Fe(DETC)2 as a spin trap. Aortas from vehicle, HSMP- and CDMP-treated mice, exhibited an EPR feature of signals derived from NO-Fe(DETC)2, being greater in aortas from active CDMP-treated mice than in vehicle- and HSMP-treated mice (Figure 6C).


Circulating microparticles from Crohn's disease patients cause endothelial and vascular dysfunctions.

Leonetti D, Reimund JM, Tesse A, Viennot S, Martinez MC, Bretagne AL, Andriantsitohaina R - PLoS ONE (2013)

Microparticles (MPs) from active CD patients induce nitric oxide (NO) overproduction in mouse aorta.Concentration-effect curves of 5-HT in the presence and in the absence of L-NA in aortic rings isolated from mice injected in vivo with vehicle (controls (CTL)) and MPs from HS (HSMPs) (A) and with MPs from active CD patients (active CDMPs) (B). Contraction are expressed in mN/mm. Results are given as mean ± SEM (n = 7–8). NO production (C) assessed by the amplitude of NO-Fe(DETC)2 complex signal and superoxide anion (O2−) production (D) assessed by the amplitude of O2–CMH complex signal in unit/weight in aorta from mice injected in vivo with vehicle (CTL), HSMPs and active CDMPs. Results are given as mean ± SEM (n = 5–7). **p<0.01; ***p<0.001 vs CTL.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3760904&req=5

pone-0073088-g006: Microparticles (MPs) from active CD patients induce nitric oxide (NO) overproduction in mouse aorta.Concentration-effect curves of 5-HT in the presence and in the absence of L-NA in aortic rings isolated from mice injected in vivo with vehicle (controls (CTL)) and MPs from HS (HSMPs) (A) and with MPs from active CD patients (active CDMPs) (B). Contraction are expressed in mN/mm. Results are given as mean ± SEM (n = 7–8). NO production (C) assessed by the amplitude of NO-Fe(DETC)2 complex signal and superoxide anion (O2−) production (D) assessed by the amplitude of O2–CMH complex signal in unit/weight in aorta from mice injected in vivo with vehicle (CTL), HSMPs and active CDMPs. Results are given as mean ± SEM (n = 5–7). **p<0.01; ***p<0.001 vs CTL.
Mentions: To investigate the role of NO, the effect of the NO-synthase inhibitor, L-NA, was studied on the response to 5-HT. Interestingly, we found that inhibition of the NO pathway did not affect response to 5-HT in vessels from HSMPs (Figure 6A) but completely prevented the vascular hypo-reactivity induced by active CDMPs (Figure 6B). Direct in situ measurements of NO production were performed by EPR spectroscopy using Fe(DETC)2 as a spin trap. Aortas from vehicle, HSMP- and CDMP-treated mice, exhibited an EPR feature of signals derived from NO-Fe(DETC)2, being greater in aortas from active CDMP-treated mice than in vehicle- and HSMP-treated mice (Figure 6C).

Bottom Line: Circulating MP levels did not differ between HS and inactive CD patients except for an increase in leukocyte-derived MPs in CD.A significant correlation was found between total levels of MPs, those from platelets and endothelial cells, and the Harvey-Bradshaw clinical activity index.CDMPs induced vascular hypo-reactivity in aorta that was prevented by a nitric oxide (NO)-synthase inhibitor, and was associated with a subtle alteration of the balance between NO, reactive oxygen species and the release of COX metabolites.

View Article: PubMed Central - PubMed

Affiliation: LUNAM Université, Angers, France ; INSERM, U1063, Angers, France.

ABSTRACT

Background: Microparticles (MPs) are small vesicles released during cell activation or apoptosis. They are involved in coagulation, inflammation and vascular dysfunction in several diseases. We characterized circulating MPs from Crohn's Disease (CD) patients and evaluated their effects on endothelial function and vascular reactivity after in vivo injection into mice.

Methods: Circulating MPs and their cellular origins were examined by flow cytometry from blood samples from healthy subjects (HS) and inactive or active CD patients. MPs were intravenously injected into mice. After 24 hours, endothelial function and vascular reactivity were assessed.

Results: Circulating MP levels did not differ between HS and inactive CD patients except for an increase in leukocyte-derived MPs in CD. Active CD patients compared to HS displayed increased total circulating MPs, pro-coagulant MPs and those from platelets, endothelium, erythrocytes, leukocytes, activated leukocytes and activated platelets. A significant correlation was found between total levels of MPs, those from platelets and endothelial cells, and the Harvey-Bradshaw clinical activity index. MPs from CD, but not from HS, impaired endothelium-dependent relaxation in mice aorta and flow-induced dilation in mice small mesenteric arteries, MPs from inactive CD patients being more effective than those from active patients. CDMPs induced vascular hypo-reactivity in aorta that was prevented by a nitric oxide (NO)-synthase inhibitor, and was associated with a subtle alteration of the balance between NO, reactive oxygen species and the release of COX metabolites.

Conclusions: We provide evidence that MPs from CD patients significantly alter endothelial and vascular function and therefore, may play a role in CD pathophysiology, at least by contributing to uncontrolled vascular-dependent intestinal damage.

Show MeSH
Related in: MedlinePlus