Since the first identification of renin by Tigerstedt and Bergmann in 1898, the renin-angiotensin system (RAS) has been extensively studied. The current view of the system is characterized by an increased complexity, as evidenced by the discovery of new functional components and pathways of the RAS. In recent years, the pathophysiological implications of the system have been the main focus of attention, and inhibitors of the RAS such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin (ANG) II receptor blockers have become important clinical tools in the treatment of cardiovascular and renal diseases such as hypertension, heart failure, and diabetic nephropathy. Nevertheless, the tissue RAS also plays an important role in mediating diverse physiological functions. These focus not only on the classical actions of ANG on the cardiovascular system, namely, the maintenance of cardiovascular homeostasis, but also on other functions. Recently, the research efforts studying these noncardiovascular effects of the RAS have intensified, and a large body of data are now available to support the existence of numerous organ-based RAS exerting diverse physiological effects. ANG II has direct effects at the cellular level and can influence, for example, cell growth and differentiation, but also may play a role as a mediator of apoptosis. These universal paracrine and autocrine actions may be important in many organ systems and can mediate important physiological stimuli. Transgenic overexpression and knock-out strategies of RAS genes in animals have also shown a central functional role of the RAS in prenatal development. Taken together, these findings may become increasingly important in the study of organ physiology but also for a fresh look at the implications of these findings for organ pathophysiology.

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IntroductionAngiotensin II (ANG II) is known to be a potent growth promoting factor for vascular smooth muscle cells and fibroblasts but little is known about its influence on growth in endothelial cells. We studied the effects of ANG II Angiotensin II (ANG II),' the main effector peptide of the renin-angiotensin system, has long been known to play an important role in the regulation of blood pressure and body fluid homeostasis. More recently, ANG II has been reported to induce hyperplasia or hypertrophy in cultured vascular smooth muscle cells derived from the aorta ( 1-4), in small resistance arteries (5) and in cardiomyocytes (6).We have previously observed that chronic oral treatment of spontaneously hypertensive rats (SHR) with an angiotensin converting enzyme inhibitor induced myocardial capillary growth independently of the antihypertensive and antihypertrophic actions of the drug (7). Theoretically, this effect could be due to a potentiation of endogenous kinins or to a reduced generation of ANG II. In the latter case, one would have to expect an antiproliferative effect of ANG II on myocardial endothelial cells which gives rise to cardiac capillaries. This hypothesis is at variance with the widely accepted idea of ANG II being a growth promoting factor in cardiovascular tissues. However, using coronary endothelial cells (CEC) from SHR and normotensive Wistar Kyoto rats in primary culture, we recently found that ANG II significantly attenuated proliferation when growth was stimulated by fetal calf serum (8, 9). Thus, in contrast to its proliferating effects on vascular smooth muscle cells (VSMC), ANG II may indeed exert antiproliferative actions on vascular endothelial cells.VSMC in culture, a common cell line to study the trophic effects of ANG II, exclusively express ATI-and no AT2-receptors (10). Therefore, ANG 11-induced growth shown in VSMC in vitro has been attributed to the ATl-receptor. The obvious discrepancy between the effects of ANG II on VSMC and on microvascular endothelial cells could be explained twofold. First, angiotensin receptors on endothelial cells could be identical to those on VSMC (i.e., ATI) but coupled to intracellular pathways different from those present in VSMC. Second, the antiproliferative response to treatment with ANG II, as observed in endothelial cells, could be due to the stimulation of an angiotensin receptor subtype different from AT1, for instance the AT2-receptor. In addition, the antiproliferative effect of ANG II could be a phenomenon occurring in serum-stimulated rat cardiac microvascular endothelial cells but not a general feature of CEC under stimulation with defined growth factors.In the present study we investigated, first, whether ANG II is antimitogenic for CEC stimulated to proliferate by the administration of a defined growth factor and second, by which angiotensin receptor subtype, ATl or AT2, the antimitogenic

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Bisphenol A (BPA), an endocrine disruptor, is employed in the manufacture of a wide range of consumer products. The suggestion that BPA, at amounts to which we are exposed, alters the reproductive organs of developing rodents has caused concern. At present, no information exists concerning the exposure of human pregnant women and their fetuses to BPA. We therefore investigated blood samples from mothers (n = 37) between weeks 32 and 41 of gestation. Afer the births, we also analyzed placental tissue and umbilical cord blood from the same subjects. We developed a novel chemical derivatization-gas chromatography/mass spectrometry method to analyze parent BPA at concentrations < 1 micro g/mL in plasma and tissues. Concentrations of BPA ranged from 0.3 to 18.9 ng/mL (median = 3.1 ng/mL) in maternal plasma, from 0.2 to 9.2 ng/mL (median = 2.3 ng/mL) in fetal plasma, and from 1.0 to 104.9 ng/g (median = 12.7 ng/g) in placental tissue. BPA blood concentrations were higher in male than in female fetuses. Here we demonstrate parent BPA in pregnant women and their fetuses. Exposure levels of parent BPA were found within a range typical of those used in recent animal studies and were shown to be toxic to reproductive organs of male and female offspring. We suggest that the range of BPA concentrations we measured may be related to sex differences in metabolization of parent BPA or variable maternal use of consumer products leaching BPA.