Endothelial function in isolated small arteries from women at reproductive age and after menopause : possibilities for improvement

Sammanfattning: Background: Alterations in vascular function are present in patients with Preeclampsia (PE) and in women after menopause. PE is a syndrome peculiar to human pregnancy that adversely affects the mother by endothelial dysfunction and the fetus due to impaired uteroplacental blood flow. It also remains a leading cause of perinatal morbidity and mortality. A current hypothesis suggests that hypoxic placenta releases one or more unidentified factors to the maternal circulation that trigger endothelial dysfunction. Women after menopause are at increased risk for cardiovascular diseases and this could be related to changes in the hormonal environment. Estrogens are considered to provide cardiovascular protection, however the exact mechanisms of action in the resistance vasculature are far from clear. Objective: The general aim of this thesis was to study endothelial function in isolated resistance arteries in order to clarify the possible causes of endothelial dysfunction and the potential for improvement in women with PE and after the menopause. In particular we aimed to evaluate if (1) microparticles (MP) from plasma of women with PE might induce endothelial dysfunction as characterized in vitro in arteries from women with PE; (2) Vascular Endothelial Growth Factor (VEGF) can induce signs of endothelial dysfunction in isolated resistance arteries from normal pregnant women; (3) 17b-estradiol (E2) have beneficial effects on endothelial function in arteries from women with PE; (4) isolated arteries from healthy postmenopausal women exhibit signs of endothelial dysfunction in contrast to premenopausal women and, if so, to compare in vitro effects of estrogenic compounds for cardiovascular protection; (5) three months of Hormonal Replacement Therapy (HRT) alters resistance artery function in isolated arteries from healthy postmenopausal women. Methodology: Normal pregnant and women with PE, pre-menopausal and post-menopausal women were recruited. Myometrial and subcutaneous resistance artery function was evaluated in-vitro using pressure- and wire-myography techniques. Endothelial function was determined by measuring flow-, endothelium-dependent and independent agonists mediated dilatation. In addition, pressure-induced myogenic responses were assessed in response to increased intraluminal pressure and vascular permeability was evaluated by applying Evans blue dye staining. Scanning electron microscopy technique was utilized for comparisons of endothelial morphology. Results and conclusions: (1) MP, isolated from plasma of women with PE induced endothelial dysfunction after an overnight incubation in isolated myometrial arteries from healthy pregnant women. In contrast, MP derived from healthy pregnant women had no effect. MP may be of importance in the etiology of endothelial dysfunction seen in PE. (2) VEGF impaired endothelium-dependent dilatation and enhanced basal tone possibly through an endothelin-1 pathway. It also increased vascular permeability similar to that found in isolated arteries from women with PE. This might indicate a potential role for VEGF in the development of endothelial dysfunction in PE. Angiopoietin-1 (Ang-1) reversed the vascular leakage induced by VEGF, suggesting that Ang-1 may have therapeutic implications in PE. (3) E2 improved flow-, but not agonist-mediated dilatation and reduced basal tone through a nitric oxide (NO)-mediated pathway in isolated myometrial arteries from women with PE. This suggests an important role for E2 to improve uteroplacental circulation in PE. Morphological signs of endothelial injury seen in arteries from women with PE support the presence of endothelial malfunctions. (4) E2 improved resistance artery function in-vitro an affect that was mimicked by selective estrogen receptor alpha (ERa) agonist propyl-pyrazole triol but not by raloxifene or genistein. This suggests that ERa might be of importance for vascular protection in the resistance circulation in women after menopause. (5) Three months supplementation with estradiol and estradiol plus medroxyprogesterone acetate, but not medroxyprogesterone acetate alone had beneficial effects on flow-mediated dilatation and endothelial morphology in isolated subcutaneous arteries from healthy postmenopausal women, suggesting combined HRT to be beneficial for resistance artery function. Significance: Studies in isolated arteries from women with PE and healthy postmenopausal women have yielded functional and morphological signs of endothelial dysfunction. We have also shown that estrogenic compounds may improve endothelial function and therefore might be of interest from a therapeutic point of view.