An MRI method for quantification of cerebral blood volume (CBV) in time-course studies of angiogenesis is described. Angiogenesis was stimulated by acclimation to hypoxia. The change in relaxation rate, R 2 , which is relatively sensitive to the microvasculature, was quantified before and after infusion of a superparamagnetic vascular contrast agent (MION). The ⌬R 2 was measured in serum and brain parenchyma with a multiecho sequence. In vitro and in vivo calibration curves of MION concentration vs. R 2 were approximated by a linear function. CBV was 3.14 ؎ 0.32% (mean ؎ SE, n ؍ 13) and 6.42 ؎ 0.54% (n ؍ 4) before and after acclimation. A second acclimated group was hemodiluted to control for polycythemia. CBV was not significantly different between hemodiluted and nonhemodiluted groups. In animals where NMR measurements were taken before and after acclimation, there was a 120% increase in CBV. The NMR technique was validated using quantitative morphometrics, which showed an increase of 147% in CBV with acclimation. We found a linear correlation between MRI and the morphometric results for CBV, as well as demonstrating a quantitative equivalence for relative changes in CBV. This article describes a simple, repeatable method of imaging brain microvascular volume using a plasma-based contrast agent that can be applied to longitudinal studies of angiogenesis. Cerebral blood volume (CBV) is known to change as a result of multiple pathophysiological conditions including, but not limited to, stroke, aging, chronic low oxygen, and cancer (1-4). In many of these states the process of angiogenesis-the generation of new capillaries from preexisting vessels-plays a significant role. Agents which change vascular susceptibility have been used to estimate CBV in a range of studies (3,(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15). Most of these studies measured relative changes in CBV and are suitable for studying conditions where regions of normal brain are available for comparison. It would be helpful, in studies where global changes in CBV may occur, such as with chemotherapy, mitochondrial disorders, birth asphyxia, or high altitude exposure, to have an absolute method of quantifying CBV. Thus, a noninvasive method for imaging CBV could be useful for studying angiogenesis in these conditions.In this article we describe an NMR imaging method suitable for quantification of CBV during time-course studies. We suggest the acronym SSTAR 2 , derived from Steady-STAte quantification of ⌬R 2 , to describe the technique. R 2 was quantified before and after infusion of the superparamagnetic intravascular agent MION (monocrystalline iron-oxide nanoparticles). Infusion of MION caused dose-dependent increases in the relaxation rates R* 2 and R 2 (8,10,12). We chose to quantify ⌬R 2 in order to remain differentially sensitive to smaller vessels (10,16). It has been previously argued, using mathematical modeling studies, that the ⌬R 2 measured before and after contrast agent infusion provides a relatively linear change with blood volume fra...
Factors regulating cerebral tissue PO2 (PtO2) are complex. With the increased use of clinical PtO2 monitors, it has become important to elucidate these mechanisms. The authors are investigating a new methodology (electron paramagnetic resonance oximetry) for use in monitoring cerebral PtO2 in awake animals over time courses of weeks. The authors used this to study cerebral PtO2 in rats during chronic acclimation to hypoxia predicting that such acclimation would cause an increase in PtO2 because of increases that occur in capillary density and oxygen carrying capacity. The average PtO2 between 7 and 21 days was increased by 228% over controls.
Estradiol is known to inhibit antigen presentation in the vagina. We report here that TGFbeta mediates the action of estradiol on vaginal antigen presenting cells (APC). When vaginal APC from ovariectomized rats were incubated with increasing concentrations of TGFbeta1 and TGFbeta2 in the presence of ovalbumin-specific T cells and ovalbumin, both TGFbeta1 and TGFbeta2 inhibited vaginal cell antigen presentation, whereas IL-6, IL-10, and TNFalpha had no consistent effect. In other experiments, estradiol-induced inhibition of antigen presentation by vaginal cells was partially reversed when vaginal APC were incubated with anti-TGFbeta antibody. In contrast, anti-TNFalpha, anti-IL-6, and anti-IL-10 had no effect on antigen presentation. The effect of anti-TGFbeta was seen with vaginal APC from ovariectomized rats treated with estradiol for 1 d as well as 3 d. Finally, analysis of TGFbeta in the culture media of vaginal cells from saline- and estradiol-treated rats indicated that the TGFbeta produced is biologically active. In response to estradiol, vaginal cell production of TGFbeta was significantly greater than that seen with control cells. These studies suggest that estradiol regulation of antigen presentation by vaginal cells is mediated through the local production of TGFbeta by vaginal cells.
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