Can Circulating Membrane Vesicles Promote Portal Hypertension?

Patients with cirrhosis have a large amount of circulating membrane vesicles—breakdown products from inflammation and liver cell damage. However, these ‘microparticles’ (MPs) are not simply debris; they contribute to the systemic vasodilation and portal hypertension associated with cirrhosis, according to the July issue of Gastroenterology.

Patients with cirrhosis have persistent vasodilation of arterial vessels, which increases portal venous inflow and contributes to portal hypertension. Some signaling pathways have been identified that contribute to these processes, but new therapeutic targets are needed.

MPs are membrane vesicles, 0.1–1 μm in diameter, that are released into the circulation when different types of cells become activated or undergo apoptosis. The MPs contain the membrane-associated proteins of the cells from which they were released, along with phosphatidylserine and other lipid components, so they might still have signaling activities and biologic effects.

Although MPs are present in everyone’s blood, they are increased in patients with vascular disorders and affect vascular tone and vascular reactivity. Pierre–Emmanuel Rautou et al. therefore analyzed levels and origins of MPs in blood samples from 91 patients with cirrhosis and 30 healthy individuals (controls).

They found that patients with cirrhosis had higher circulating levels of MPs from leuko-endothelial cells (CD31+/41), pan-leukocyte cells (CD11a+), lymphocytes (CD4+), and erythrocytes (CD235a+), compared with controls. Plasma samples from patients with cirrhosis contained hepatocyte-derived MPs (cytokeratin-18+), whereas plasma from controls did not.

Futhermore, the circulating levels of MPs of leuko-endothelial (CD31+/41) and hepatocyte origin (cytokeratin-18+) increased with severity of cirrhosis. Rautou et al. propose that the increase resulted from release of MPs during the hepatocyte apoptosis that occurs in chronic liver disease.

Ex vivo, MPs isolated from patients with advanced cirrhosis impaired contraction of rat aortic vessels in response to vasoconstrictors such as phenylephrine, whereas MPs from controls or patients with early-stage cirrhosis (Child–Pugh class A) did not. The authors conclude that MPs induce vascular hypocontractility and contribute to the systemic vasodilation observed in patients with cirrhosis.

The ability of MPs to impair vascular contraction required cyclooxygenase (COX)-1 and MP surface phosphatidylserine. Membrane phospholipids might therefore be transferred from the MPs to endothelial cells, where they act as substrate for phospholipase A2 (PLA2) production of arachidonic acid metabolites (see figure).

Proposed mechanism of MP regulation of systemic vascular tone in portal hypertension. MPs are released from cells and fuse with systemic vascular endothelial cells. Membrane lipids derived from fused MP are metabolized by PLA2 into arachidonic acid metabolites, which are secreted and promote vascular smooth muscle hyporeactivity to vasoconstrictors. This leads to the hyperdynamic vascular phenotype that characterizes cirrhosis. Inset box shows other mechanisms by which lipid membranes (exosomes, MPs, or apoptotic bodies) are released and affect other cells.

Injecting MPs from patients with cirrhosis into mice decreased their mean arterial blood pressure, even following injection of phenylephrine.

Interestingly, Rautou et al. observed that MPs also carried soluble cytokeratin-18. The MP-bound cytokeratin-18 better correlated with severity of liver disease and systemic inflammation than total soluble cytokeratin-18. MP-bound cytokeratin-18 could be a useful marker of severity of cirrhosis.

In an editorial that accompanies the article, Juan Carlos Garcia–Pagán and Vijay H. Shah say that previous studies have focused largely on paracrine factors released by endothelium that act on smooth muscle, whereas Rautou et al. have identified a new mechanism of paracrine signaling that contributes to vasodilatation and portal hypertension in cirrhosis.

Garcia-Pagan and Shah discuss how the roles of MP in chronic liver disease could go beyond their effects on systemic hemodynamics observed by Rautou et al. For example, MP might also function as pro-coagulants, providing a membrane surface for the assembly of components of the coagulation cascade.

Read the article online.
Rautou P-E, Bresson J, Sainte-Marie Y, et al. Abnormal plasma microparticles impair vasoconstrictor responses in patients with cirrhosis. Gastroenterology 2012;143:166–176.e6.

Read the accompanying editorial.
Garcia-Pagán JC, Shah VH. Microparticles and paracrine signaling in portal hypertension: crucial conversations or idle chat? Gastroenterology 2012;143:22–25.

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