Gastroenterology

Gastroenterology

Volume 143, Issue 1, July 2012, Pages 166-176.e6
Gastroenterology

Original Research
Basic and Translational—Liver
Abnormal Plasma Microparticles Impair Vasoconstrictor Responses in Patients With Cirrhosis

https://doi.org/10.1053/j.gastro.2012.03.040Get rights and content

Background & Aims

Circulating membrane-shed microparticles (MPs) participate in regulation of vascular tone. We investigated the cellular origins of MPs in plasma from patients with cirrhosis and assessed the contribution of MPs to arterial vasodilation, a mechanism that contributes to portal hypertension.

Methods

We analyzed MPs from blood samples of 91 patients with cirrhosis and 30 healthy individuals (controls) using flow cytometry; their effects on the vascular response to vasoconstrictors were examined in vitro and in vivo.

Results

Circulating levels of leuko-endothelial (CD31+/41), pan-leukocyte (CD11a+), lymphocyte (CD4+), and erythrocyte (CD235a+) MPs were higher in patients with cirrhosis than in controls. Plasma of patients with cirrhosis contained hepatocyte-derived MPs (cytokeratin-18+), whereas plasma from controls did not. The severity of cirrhosis and systemic inflammation were major determinants of the levels of leuko-endothelial and hepatocyte MPs. MPs from patients with advanced cirrhosis significantly impaired contraction of vessels in response to phenylephrine, whereas MPs from healthy controls or from patients of Child–Pugh class A did not. This effect depended on cyclooxygenase type 1 and required phosphatidylserine on the surface of MPs. Intravenous injection of MPs from patients with cirrhosis into BALB/C mice decreased mean arterial blood pressure.

Conclusions

Cirrhosis is associated with increases in circulating subpopulations of MPs, likely resulting from systemic inflammation and liver cell damage. The overall pool of circulating MPs from patients with advanced cirrhosis impairs vasoconstrictor responses and decreases blood pressure, contributing to the arterial vasodilation associated with portal hypertension.

Section snippets

Patients and Controls

We included 91 patients admitted to the Liver Unit (Hôpital Beaujon, Clichy, France) for alcoholic and/or hepatitis C virus–related cirrhosis during 2 periods: 26 patients between 2007 and 2008 (the pilot cohort) and 65 additional patients between 2010 and 2011 (Figure 1A). None of the patients had severe sepsis, hepatocellular carcinoma assessed using serum α-fetoprotein level and computed tomographic scan or ultrasonography, or portal vein thrombosis. The pilot cohort was compared with a

Cellular Origin of MPs From Patients With Cirrhosis

We first compared circulating MP levels and cellular origins in the 26 patients with cirrhosis from the pilot cohort and in 30 healthy controls (Figure 1A). Age and prevalence of cardiovascular risk factors were not different between patients and controls except for a lower prevalence of dyslipidemia and a lower body mass index in the former group (Supplementary Table 1). Despite this lower prevalence of dyslipidemia and a lower body mass index (dyslipidemia and obesity being known to be

Discussion

The present study shows that the plasma of patients with cirrhosis contains high levels of MPs of leuko-endothelial, lymphocyte, erythrocyte, and hepatocyte origin. Circulating MPs from patients with advanced cirrhosis contribute to systemic vasodilation of cirrhosis. Indeed, they are taken up by endothelial cells and induce arterial hyporeactivity to vasoconstrictor agents in a phosphatidylserine- and COX-1–dependent manner.

One strength of this study is the procedure to isolate MPs and the

Acknowledgments

The authors thank Emmanuelle Hoareau for Western blotting analysis; Claire Crequit, Johanna Erbani, and Jérémy Scetbun for vascular reactivity experiments; Nathalie Colnot for histologic analysis; Sonia Bergaya and Coralie Guerin for advice; Anthony C. Allison (Alavita Pharmaceuticals, Mountain View, CA) for providing diannexin and for helpful discussions; Professor Philippe Marteau and Drs Samy Boussoukaya, Safi Dokmak, Samir Fteriche, Pauline Houssel, Séverine Poupeney, Marie-Pierre Ripault,

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    Conflicts of interest The authors disclose no conflicts.

    Funding Supported by the Institut National de la Santé et de la Recherche Médicale, Plan National de Recherche en Hépato-gastroentérologie 2007 (A07146SP), Société Nationale Française de Gastroentérologie, Association Française pour l'Étude du Foie, and Université Paris 7 (Projets interdisciplinaires Paris Diderot, 2009). P-E.R. was supported by “bourse d'appui Société Nationale Française de Gastroentérologie - Sanofi-Aventis” and by the “poste d'accueil INSERM,” J.B. by Association Amicale des Anciens Internes en Médecine des Hôpitaux de Paris (A.A.I.H.P.), A-C.V. by CODDIM Ile de France, and C.M.B. and R.M. by a “Contrat d'Interface Assistance Publique Hôpitaux de Paris.”

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