New insights into the control of small artery function in human pregnancy and estrogen receptor beta knockout mice

Background: Available data clearly indicates functional and morphological differences between small and large arteries, and observations from studies on large arteries may not be applicable to understand the physiology of small arteries (~200-300mum) that actively participate in the regulation of peripheral vascular resistance, blood pressure and flow to target organs. These events confer cardiovascular adaptation to normal pregnancy (NP), however they are disturbed in preeclampsia (PE) and in estrogen receptor beta knockout (ERbetaKO) mice at a certain age. Aims: (1) To assess endothelial function and morphology with focus on the role and mechanisms of endothelium-derived hyperpolarizing factor (EDHF)-mediated relaxation in small subcutaneous arteries isolated from pregnant women with and without PE; (2) To estimate the predisposition for sex difference in blood pressure of ERbetaKO mice at the level of small arteries function with a focus on endothelium-dependent dilatation (EDHF) and adrenergic vasoconstriction. Methodology: Small subcutaneous arteries obtained from pregnant women and femoral arteries obtained from age-matched (14-22 weeks old) female and male wild type (WT, ERbeta +/+) and ERbetaKO mice were used in a wire-myography set-up for functional studies. Immunohistochemistry for connexins (Cx) and/or ER subtypes (as appropriate), as well as scanning and transmission electron microscopy techniques were also utilized for evaluation of small arteries morphology with particular focus on prerequisite for gap junction communications. Results and conclusions: (1) The overall endothelium-dependent response in arteries from pregnant women with and without PE was similar. However, EDHF-mediated relaxation was reduced in PE. The results demonstrated heterogeneity in the relative contribution of endothelium-derived factors and in the mechanisms responsible for the EDHF-mediated relaxation in PE. Gap junctions and/or H2O2 and/or cytochrome P450 epoxygenase metabolites of arachidonic acid appeared to be involved in the EDHF-mediated response in PE. In NP women, communication via gap junctions via Cx 43 represented a common pathway responsible for EDHF action. The link between morphological alterations within the vascular wall, and changes in the contribution of gap junctions to EDHFmediated relaxation of small arteries isolated from women with PE was suggested. (2) Endothelium-dependent relaxation in arteries (