Small artery endothelial dysfunction in postmenopausal women:: In vitro function, morphology, and modification by estrogen and selective estrogen receptor modulators

Objective: Our objective was to assess vascular endothelial function and morphology in resistance vasculature from healthy pre- and postmenopausal women in vitro and to determine potential mechanisms of vascular protection by estrogenic compounds. Methods: Arteries (similar to 220 mu m) were dissected from sc fat biopsies obtained from healthy premenopausal and postmenopausal women. Flow-mediated dilatation, agonist-induced endothelium-dependent and -independent relaxation, and myogenic responses to changes in intraluminal pressure were evaluated before and after incubation (3 h) with 17 beta-estradiol, propyl pyrazole triol [a selective estrogen receptor-alpha (ER alpha) agonist], raloxifene (a second- generation selective ER modulator), and the phytoestrogen genistein, using pressure myography technique. In addition, endothelial morphology was assessed in arteries from pre- and postmenopausal women, and distribution of ERs within the artery wall from postmenopausal women was evaluated. Results: Functional and morphological disturbances of endothelial function were observed in small arteries from postmenopausal women. Incubation with 17 beta-estradiol improved postmenopausal resistance artery function, an effect mimicked by propyl pyrazole triol but not raloxifene or genistein. Immunohistochemical staining revealed similar expression of ER alpha and ER beta in the smooth muscle of arteries from postmenopausal women; however, ER alpha was dominant in endothelium. The resistance arteries from postmenopausal women show functional and morphological abnormalities. ER alpha may contribute to vascular protection by estrogens in the peripheral resistance circulation in postmenopausal women. Selective ER alpha agonists warrant further investigation as therapeutic agents for prevention of cardiovascular disease in postmenopausal women.