The mechanism of EDHF-mediated responses in subcutaneous small arteries from healthy pregnant women

Abstract

Luksha, Leonid, Henry Nisell, and Karolina Kublickiene. The mechanism of EDHF-mediated responses in subcutaneous small arteries from healthy pregnant women. Am J Physiol Regul Integr Comp Physiol 286: R1102-R1109, 2004. First published January 29, 2004 10.1152/ajpregu.00550.2003.-We studied the importance of endothelium-derived hyperpolarizing factor (EDHF) vs. nitric oxide (NO) and prostacyclin (PGI2) in bradykinin (BK)-induced relaxation in isolated small subcutaneous arteries from normal pregnant women. We also explored the contribution of cytochrome P-450 (CYP450) product of arachidonic acid (AA) metabolism, hydrogen peroxide (H2O2), and gap junctions that have been suggested to be involved in EDHF-mediated responses. Isolated arteries obtained from subcutaneous fat biopsies of normal pregnant women (n ϭ 30) undergoing planned cesarean section were mounted in a wire-myography system. In norepinephrine-constricted vessels, incubation with N G -nitro-Larginine methyl ester (L-NAME) resulted in a significant reduction in relaxation to BK. Simultaneous incubation with L-NAME and indomethacin failed to modify this response further. BK-mediated dilatation in the presence of K ϩ -modified solution was decreased to similar level as obtained after incubation with L-NAME. Incubation with L-NAME abolished BK-induced responses in K ϩ -modified solution. Sulfaphenazole, a specific inhibitor of CYP450 epoxygenase, and catalase (an enzyme that decomposes H2O2) did not affect the EDHFmediated relaxation because concentration-response curves to BK were similar in arteries after incubation with L-NAME vs. L-NAME ϩ sulfaphenazole and L-NAME ϩ catalase. The inhibitor of gap junctions, 18␣-glycyrrhetinic acid, significantly reduced BK-mediated relaxation both without and with incubation with L-NAME. We found that both NO and EDHF, but not PGI2, are involved in the endothelium-dependent dilatation to BK. BK-induced relaxation is almost equally mediated by NO and EDHF. CYP450 epoxygenase metabolites of AA or H2O2 do not account for EDHF-mediated response; however, gap junctions are involved in the EDHF-mediated responses to BK in subcutaneous small arteries in normal pregnancy. endothelium-dependent relaxation; gap junctions; endothelium-derived hyperpolarizing factor; hydrogen peroxide MATERNAL CARDIOVASCULAR ADAPTATION to normal pregnancy is associated with decreased peripheral vascular resistance that plays an important role for blood pressure reduction despite an increase in plasma volume and cardiac output. The vascular adaptation to normal pregnancy is believed to be dependent on an enhanced endothelium-dependent dilatation (3,18,25). However, the pathways underlying these changes are not fully understood and need further investigation because an impaired cardiovascular adaptation is associated with the development of preeclampsia (18,25,42). It is generally accepted that preeclampsia is an endothelial cell disorder, and the increased vascular resistance and blood pressure during this pregnancyrelated disease are due to en...

Estrogen replacement enhances EDHF-mediated vasodilation of mesenteric and uterine resistance arteries: role of endothelial cell Ca2+

“…These differences most likely result from an increasing contribution of EDHF in the control of vascular tone in the uterine and mesenteric circulation with decreasing vessel size. Our data are in agreement with ample evidence that EDHF is an important mediator of endothelial influences in microcirculation of animals and humans (6,7,9,11,13,25,28,30,33,36,(45)(46)(47).…”

Sex differences in vascular function: implication of endothelium-derived hyperpolarizing factor

“…Indeed, it has been proposed that a decrease in the vascular expression of Cx43 alone or concomitantly with Cx40 could afford the reduction in EDHF-mediated responses in rat mesenteric arteries of ovariectomized rats , Xu et al 2002, Nawate et al 2005; this was substantiated by the observation that when animals were treated with 17b-estradiol, all responses were normalized (Chataigneau & Schini-Kerth 2005, Nawate et al 2005. In addition, it has been suggested that the increased EDHFmediated relaxation, associated with pregnancy in rats and humans (Pascoal & Umans 1996, Gerber et al 1998, Kenny et al 2002, is in part due to enhanced gap junctional communication at least in response to bradykinin in subcutaneous small arteries of pregnant women (Luksha et al 2004, Lang et al 2007). However, in rat middle cerebral arteries myoendothelial gap junction frequency does not correlate with the reduced EDHF responses observed in females compared with males (Sokoya et al 2007).…”

Maternal Vascular Physiology in Preeclampsia

“…MEGJs and the gap junction protein, Cx43 (connexin 43), are the primary mechanisms underlying EDH in small resistance arteries isolated from subcutaneous fat biopsies from normal pregnant women. 37,38 The function of MEGJ was deficient in arteries from women with preeclampsia, contributing to reduced EDH involvement in dilatory responses to bradykinin. 39 Total relaxation to bradykinin, however, did not differ between normal pregnant and preeclamptic women.…”