Estrogen receptor beta: Influence on urokinase-type plasminogen activator in vascular smooth muscle cells

Abstract

It has been proposed that the presence or administration of 17-beta estradiol can be protective against heart disease, the primary cause of death for both men and women. Acute events in the progression of atherosclerosis are thought to be primarily the result of plaque rupture, a mechanical event dependent on the structural integrity of a lesion. The mechanism by which 17-beta estradiol confers vascular benefits may be related to expression or activation of structural proteins and degradative enzymes influencing plaque composition and stability. Ligand signaling by 17-beta estradiol is thought to occur via specific estrogen receptors (ERs) expressed in the cell membrane of vascular cells. The aim of this thesis was to investigate the influence of ERs on the activity of uPA, a protease that is capable of degrading structural proteins integral to atherosclerotic plaque stability. Vascular smooth muscle cell (VSMC) uPA activity was observed after treatment with 17-beta estradiol, 4-hydroxytamoxifen, faslodex (ICI 182,780) and antisense to ERbeta, the most recently discovered ER. The addition of ER ligands 4-hydroxytamoxifen and faslodex resulted in a substantial increase in the activity of uPA. This effect was determined to be dependent on transcription, translation and N-glycosylated secretion. However, these effects were independent of transcriptional events involving the estrogen response element. Therefore, the ERs may be acting via AP-1 or Sp1 enhancer regions controlling transcription. Alternatively a signal for the release of pro-uPA from secretory granules may be transmitted via cell surface ERs.