Role of kinins in mediating vascular function in healthy pregnancy and pre-eclampsia

Abstract

Pre-eclampsia is a pregnancy-related disorder characterised by high blood pressure, proteinuria and oedema. The aetiology of the disease is unclear but evidence suggests that endothelial dysfunction is central to the development of the maternal syndrome. Kinins are endogenous peptides released by the endothelium that contribute to the regulation of cardiovascular homeostasis by inducing vasodilation, fibrinolysis and angiogenesis. Given that pre-eclampsia is associated with reduced endotheliumdependent relaxation, coagulation abnormalities and an angiogenic imbalance, it was hypothesised that alterations of kinin receptor-mediated responses may be involved in the pathogenesis of the condition. To investigate whether changes in kinin receptor activity are involved in the impairment of endothelium-dependent relaxation observed in pre-eclampsia, the effects of specific B2 and B1 receptor agonists and antagonists on myometrial vascular tone were tested on arteries from healthy pregnancy and pre-eclampsia. The results demonstrated that in addition to classical bradykinin B2 receptor-mediated relaxation, a subset of healthy patients exhibited nitric oxide-dependent relaxation to the B1 receptor agonist Lys-des- Arg9-BK (LDABK) which could not be inhibited by either B1 or B2 receptor antagonists. Also, vessels that exhibited this novel response to LDABK were more sensitive to bradykinin. Furthermore, this study revealed that patients with pre-eclampsia had an attenuated response to both bradykinin and LDABK. Immunolocalisation and mRNA expression of the kinin receptors in the myometrium revealed no differences between healthy pregnancy and pre-eclampsia suggesting that disturbances of kinin receptor signalling rather than changes in receptor distribution or expression levels may be involved in the reduction of kinin-mediated responses in these patients. The role of kinins in mediating placental angiogenesis in healthy pregnancy and preeclampsia was determined using the endothelial tube formation assay in primary human umbilical vein endothelial cells (HUVECs) isolated from healthy women and women with pre-eclampsia. B2 and B1 receptor agonists induced endothelial tube formation via a VEGF-dependent, nitric oxide-independent mechanism in healthy HUVECs cultured in normoxic conditions. HUVECs isolated from women with pre-eclampsia cultured under normoxia and HUVECs from healthy pregnancies cultured under hypoxia exhibited greater levels of angiogenic branching compared with healthy normoxic cells, but were unresponsive to bradykinin and LDABK. Incubation of these cells with a VEGF receptor inhibitor reduced the elevated levels of tube formation indicating that this effect may be due to hypoxic upregulation of VEGF or an intrinsic difference in their angiogenic capacity. Further studies are required to determine the cause for the differences in angiogenic potential between healthy and pre-eclamptic cells and the impact this could have on placental vascular development and the pathogenesis of preeclampsia.