Plasma from patients with HELLP syndrome increases blood-brain barrier permeability

Abstract

Circulating inflammatory factors and endothelial dysfunction have been proposed to contribute to the pathophysiology of hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome. To date, the occurrence of neurological complications in these women has been reported, but few studies have examined whether impairment in blood-brain barrier (BBB) permeability or cerebrovascular reactivity is present in women having HELLP syndrome. We hypothesized that plasma from women with HELLP syndrome causes increased BBB permeability and cerebrovascular dysfunction. Posterior cerebral arteries from female nonpregnant rats were perfused with 20% serum from women with normal pregnancies (n = 5) or women with HELLP syndrome (n = 5), and BBB permeability and vascular reactivity were compared. Plasma from women with HELLP syndrome increased BBB permeability while not changing myogenic tone and reactivity to pressure. Addition of the nitric oxide (NO) synthase inhibitor N(ω)-nitro-L-arginine methyl ester caused constriction of arteries that was not different with the different plasmas nor was dilation to the NO donor sodium nitroprusside different between the 2 groups. However, dilation to the small- and intermediate-conductance, calcium-activated potassium channel activator NS309 was decreased in vessels exposed to HELLP plasma. Thus, increased BBB permeability in response to HELLP plasma was associated with selective endothelial dysfunction.

Keywords: HELLP syndrome; blood–brain barrier permeability; myogenic response.

Figure 1.

Plasma from women with HELLP syndrome increases BBB permeability compared to plasma from normal pregnant women. The permeability parameters intravascular pressure drop, volume flux, J_v/S, and L_p were used to determine BBB permeability in cerebral arteries from nonpregnant female rats perfused with the different plasmas. A, Decrease in intravascular pressure in response to plasma from women with HELLP syndrome was significantly greater compared to the normal pregnant group. B, Plasma from women with HELLP syndrome tended to have an increase in flux compared to the normal pregnant group. C, Plasma from women with HELLP syndrome caused a significant increase in J_v/S compared to plasma from normal pregnant women. D, There was a significant increase in L_p in response to the HELLP plasma. *P < .05 compared to normal pregnant plasma. BBB indicates blood–brain barrier; HELLP, hemolysis, elevated liver enzymes, and low platelet count.

Figure 2.

The effect of HELLP and control plasma on myogenic activity and tone. Graphs showing (A) that vessels perfused with plasma from women with normal pregnancies or HELLP syndrome had myogenic reactivity and maintained their diameters as pressure increased that was not different with the different plasmas (B) that the different plasmas did not affect the level of pressure-induced tone. HELLP indicates hemolysis, elevated liver enzymes, and low platelet count.

Figure 3.

The effect of hemolysis, elevated liver enzymes, and low platelet count (HELLP) plasma on reactivity to NO. A, The constriction in response to nitric oxide synthase (NOS) inhibition with 10^{− 3} mol/L N^ω-nitro-l-arginine methyl ester (l-NAME) was not different with the different plasmas. B, The sensitivity to the NO donor sodium nitroprusside (SNP) in posterior cerebral artery (PCA) was unchanged between the 2 groups. NO indicates nitric oxide.

Figure 4.

The effect of HELLP plasma on sensitivity to small- and intermediate-conductance Ca²⁺-activated K⁺ (SK/IK) channel activation with NS309. A, Plasma from women with HELLP syndrome significantly decreased sensitivity to NS309 dilation and (B) shows that the half maximal effective concentration (EC₅₀) values for NS309 were significantly increased in arteries exposed to HELLP plasma. *P < .05 versus normal pregnant plasma. HELLP indicates hemolysis, elevated liver enzymes, and low platelet count.