The protective effects of estrogens in the cardiovascular system of women may be due to the genomic effects of ERbeta in vascular tissue.

Variant PR and ER transcripts are extensively expressed in human vascular smooth muscle. The complex tissue-specific effects of sex hormones may be mediated by the expression of heterogeneous forms of their cognate receptors. The presence of variant ERs and PRs may be of importance in altering the physiological effects of estrogens or progestins in vascular smooth muscle.

Proliferation of vascular smooth muscle cells (VSMC)is characteristic of restenosis following balloon angioplasty. We show here that a low concentration of a novel iron chelator, desferri-exochelin 772SM, reversibly arrests the growth of human VSMC in vitro, specifically in G 0 /G 1 and S phases. The lipophilic desferri-exochelin is effective more rapidly and at a 10-fold lower concentration than the nonlipophilic iron chelator deferoxamine. Treatment of growth-synchronized VSMC with the desferri-exochelin results in down-regulation of cyclin E/ Cdk2 and cyclin A/Cdk2 activity but does not affect the cyclin D/Cdk4/retinoblastoma phosphorylation pathway. Both DNA replication and RNA transcription are inhibited in exochelin-treated cells, but protein synthesis is not. The ability of desferri-exochelin 772SM to reversibly block the growth of VSMC in vitro with no apparent cytotoxicity suggests that the exochelin may be useful as a therapeutic agent to limit restenosis in injured vessels.Although vascular smooth muscle cells (VSMC) 1 are normally quiescent, they enter the cell cycle when exposed to growth factors in vitro or following vascular injury in vivo. In animal models, proliferation and migration of VSMC begin soon after vascular injury occurs and culminate in formation of a neointima that encroaches on the interior space of the vessel (1). Such neointima formation is seen in a substantial number of patients following balloon angioplasty and may result in a narrowing or blockage (restenosis) of the vessel that requires further intervention (2). By preventing the immediate proliferation of VSMC following vascular injury, it may be possible to avert neointima formation and restenosis. In this report, we describe the cell cycle-specific growth inhibitory effects of a novel iron chelator, desferri-exochelin 772SM, on serum-and growth factor-stimulated human VSMC in vitro.Iron is required for a variety of cellular functions, including respiration, energy metabolism, and DNA synthesis. In addition, iron participates in redox reactions that generate free radicals, which may activate signaling pathways for cell proliferation. Treatment with iron chelators has previously been shown to cause growth arrest in several types of cells (3-5). However, the effect of chelation varied depending upon both the cell type and the chelator used (5-7).The iron chelator deferoxamine (DFO) inhibited DNA synthesis in cultured rat VSMC (8) and blocked neointimal growth in a rat model of vascular injury (8). However, DFO enters cells only very slowly by pinocytosis (9) and causes hypotension when given in large doses in vivo (10). Therefore, DFO is of limited usefulness for determining mechanisms by which iron deprivation prevents cell cycle progression or for the clinical treatment of restenosis.Exochelins, the secreted siderophores of Mycobacterium tuberculosis, are a family of high affinity iron chelators that are both water-and lipid-soluble, a property that allows them to enter cells rapidly and chelate specific intracellular iro...

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