Regulation of vascular tone in myometrial resistance arteries in normal pregnancy and preeclampsia

Abstract

Background: Normal pregnancy is characterized by the occurrence of substantial vasodilatation. Pressure responsiveness and vascular reactivity to administered vasoconstrictors undergo considerable attenuation. These circulatory changes are essential to maintain adequate oxygen and nutrient delivery to the placenta and thus to the fetus. Preeclampsia (PE) is a syndrome associated with widespread endothelial dysfunction and an increased peripheral vascular resistance, mainly affecting the renal and uteroplacental circulations. The physiology and pathophysiology underlying the vascular adaptation in human pregnancy is not fully elucidated, and improvement of our knowledge in this field is of the utmost importance.

Vasoactive factors produced by vascular endothelium and alterations in vascular wall function are possible candidates as mediators of these circulatory changes. There is increasing evidence that the release of the endothelium-derived relaxing factors, nitric oxide (NO), prostacyclin (PGI2), and the constricting factor, endothelin-l (ET-I), is altered during normal pregnancy and pregnancy complicated by PE and may therefore significantly contribute to these changes. As blood flows through the lumen of a vessel, it exerts a mechanical force (i.e. shear stress) on endothelial cells. Endothelial cells can respond to shear stress by releasing endothelium-derived factors, particularly NO and PGI2 In addition to shear stress, changes in intra vascular pressure may also contribute to the regulation of vascular tone. Although myogenic in origin, pressure-induced tone may be modulated by endothelium derived factors.

Objective: The purpose of the studies upon which this thesis is based was to study the effects of endothelium-derived factors, pressure and flow in the modulation of vascular tone in myometrial resistance arteries in normal pregnant women and women with PE. Owing to the putative involvement of endothelium derived factors in the regulation of vascular tone in uterine circulation, a considerable emphasis was placed on in vitro studies of myometrial resistance arteries which are directly involved in the regulation of uterine blood flow to the placenta during normal pregnancy and PE.

Methods: Two different in vitro experimental approaches (i.e. isometric and isobaric) were adopted in these studies. The isometric wire-mounted artery system was used initially to evaluate vascular contractile responses to ET-I, and the interaction of ET-l with substances mediating vasodilatation, such as atrial natriuretic peptide (ANP) and cyclic guanosine monophosphate (cGMP), the Ca2+ channel blocker, is radipine, and the ETA receptor antagonist, BQ-123. The perfusion myography (isobaric) system is more representative of the in vivo situation than is the wire mounted artery system, and allows assessment of the effect of pressure and flow on vascular tone.

Major findings and conclusions: ET-l is a potent vasoconstrictor of myometrial arteries in both normal and preeclamptic gravidae, and the contractile effect is mediated by ETA receptors. The ET-I induced contractile activity was attenuated to a small extent by is radipine. Both ANP and cGMP, the latter a second messenger for both ANP and NO, caused relaxation of ET-I preconstricted myometrial resistance arteries. Shear stress and pressure are important regulators of vascular tone in the uterine circulation in normal human pregnancy. Pressure-induced myogenic tone and flow-induced dilatation are modulated by endothelium-derived factors such as NO and ET-I. In preeclampsia, the pressure-induced myogenic constriction in combination with impaired endothelium-dependent dilatation, as reflected by impaired acetylcholine release and diminished shear stress mediated NO release, may contribute to the increased vascular resistance in the uteroplacental circulation. This suggests that NO may play a fundamental part in the maintenance of adequate blood supply to the fetus during human pregnancy.

Significance: The functional studies in isolated myometrial artery preparations have yielded an increased knowledge of the mechanisms responsible for the regulation of uteroplacental vascular resistance in normal pregnancy and preeclampsia, specifically with respect to the effects of intraluminal pressure and flow and the part that endothelium-derived factors may play. The results may have implications for the future development of therapeutic tools for use in PE.