The role of matrix metalloproteinases in vascular function: implications for normal pregnancy and pre‐eclampsia

Abstract

Objectives (1) To investigate the effects of plasma from non-pregnant, normal pregnant and pre-eclamptic women on myogenic tone and endothelium-dependent relaxation; (2) To investigate the role of matrix metalloproteinases (MMPs) in these parameters of vascular function. Design Analysis of the effects of plasma from non-pregnant, normal pregnant and pre-eclamptic women on myogenic tone and endothelium-dependent relaxation, and the effects of MMP inhibition on these parameters. Setting University of Alberta, Edmonton, Alberta, Canada.Samples Pooled plasma from non-pregnant (n ¼ 9), normal pregnant (n ¼ 6) and pre-eclamptic women (n ¼ 12).Methods Mesenteric arteries from virgin female C57BL/6J mice were exposed to pooled plasma from nonpregnant, normal pregnant and pre-eclamptic women in the absence and presence of GM6001 (5 AM; MMP inhibitor), and arterial function was assessed. Main outcome measures Myogenic tone and endothelium-dependent relaxation.Results Plasma of women with pre-eclampsia, and interestingly, plasma of non-pregnant women, significantly enhanced myogenic tone at pressures !70 mmHg (P < 0.001) and blunted the maximum relaxation to methacholine (P < 0.001; P < 0.005) in isolated arteries. GM6001 altered response only in vessels exposed to the plasma of women with pre-eclampsia; however, contrary to our hypothesis, this further enhanced myogenic tone and further abrogated relaxation. Conclusions The strikingly similar vascular function profiles of vessels incubated in the plasma of nonpregnant and pre-eclamptic women suggest that pre-eclampsia may be due, in part, to the lack of a necessary adaptation to pregnancy. Despite these similarities, however, there are differential effects of MMP inhibition, suggesting that MMPs play a greater role in the vasculature of women with pre-eclampsia compared with non-pregnant and normal pregnant women.

Altered endothelial function in isolated human myometrial vessels induced by plasma from women with pre-eclampsia is not reproducible in isolated mouse vessels

“…Furthermore, the lack of effect of plasma from women with pre-eclampsia on mice vessels was consistent for all the vascular beds studied; there was no effect of gender, vessel origin or pregnancy. These findings contrast with the previously reported observation that plasma from women with pre-eclampsia is capable of altering endothelial function in isolated mouse arteries [16,17].…”

“…Given that the aetiology of pre-eclampsia is well known to be broad and poorly defined, in terms of clearly identifiable biological effectors, it is perhaps not surprising that a range of effects may be observed when testing the suitability of a biological assay. Certainly results from our present study, and those of Gandley et al [16] and Merchant et al [17], indicate that further experimentation is required before the relaxation of mouse arteries can be used as an indicator of the biological activity of plasma from women with preeclampsia. This highlights the need for collaborative studies involving the assessment of plasma collected from patients in different laboratories.…”

“…Gandley et al [16], and more recently Merchant et al [17], however, reported that plasma from women with pre-eclampsia was capable of inducing alterations in endothelial function in mouse mesenteric vessels using perfusion myography. Therefore the aim of the present study was to determine whether vessels isolated from C57B mice would serve as a suitable model for extensive characterization studies of the bioactivity of plasma from women with pre-eclampsia.…”

Increased Expression of Matrix Metalloproteinase-1 in Systemic Vessels of Preeclamptic Women

“…19,20,58 Our data demonstrate that active MMP-1 is also a regulator of vascular reactivity. Therefore, increasing levels of MMP-1 in preeclampsia seem to be central to the hypertensive disorder observed in these women.…”

Big ET-1 processing into vasoactive peptides in arteries and veins

“…ET-1 functions as a vasoconstrictor in rat mesenteric arteries, and a potential vasodilator in rat renal arteries via activation of ET B receptors. Thus, the endogenous metabolism of big ET-1 via MMP leads to the possibility of production of an additional vasoactive ET peptide [4,5,10,20,23,24,28]. Similarly, the enzyme chymase can metabolize big ET-1 to ET-1 [7,12,13,14,15,21,25,37].…”