Angiotensin II and VEGF are Involved in Angiogenesis Induced by Short-Term Exercise Training

Results from our laboratory have suggested a pathway involving angiotensin II type 1 (AT1) receptors and vascular endothelial growth factor (VEGF) in angiogenesis induced by electrical stimulation. The present study investigated if similar mechanisms underlie the angiogenesis induced by short-term exercise training. Seven days before training and throughout the training period, male Sprague-Dawley rats received either captopril or losartan in their drinking water. Rats underwent a 3-day treadmill training protocol. The tibialis anterior and gastrocnemius muscles were harvested under anesthesia and lightly fixed in formalin (vessel density) or frozen in liquid nitrogen (VEGF expression). In controls, treadmill training resulted in a significant increase in vessel density in all muscles studied. However, the angiogenesis induced by exercise was completely blocked by either losartan or captopril. Western blot analysis showed that VEGF expression was increased in the exercised control group, and both losartan and captopril blocked this increase. The role of VEGF was directly confirmed using a VEGF-neutralizing antibody. These results confirm the role of angiotensin II and VEGF in angiogenesis induced by exercise

Distinct roles of estrone and estradiol in endothelial colony-forming cells.

Our current understanding of the relationship between estrogen and human endothelial colony-forming cell (hECFC) function is based almost exclusively on studies investigating estradiol action at nuclear estrogen receptors. In the current study the hypothesis was tested that the less potent estrogen receptor agonist, estrone, affects hECFC proliferation, migration, secretion, and tube formation in a way that is unique from that of estradiol. The relationship between the estrogens, estradiol and estrone, is clinically important, particularly in postmenopausal women where estradiol levels wane and estrone becomes the predominant estrogen. Cultured hECFCs from peripheral blood mononuclear cell fractions were treated with concentrations of estradiol and estrone ranging from 1 nM to 1 μM separately and in combination. Following treatment, proliferation, migration, ability to attract other hECFCs (autocrine secretion), and ability to enhance endothelial cell tube formation (tubulogenesis) were tested. Functional assays revealed unique, concentration-dependent physiological effects of estrone and estradiol. Estradiol exposure resulted in increased hECFC proliferation, migration, secretion of chemoattractant, and enhancement of tube formation as expected. As with estradiol, hECFC secretion of chemoattractant increased significantly with each increase in estrone exposure. Estrone treatment produced a biphasic, concentration-dependent relationship with proliferation and tube formation and relatively no effect on hECFC migration at any concentration. The quantitative relationship between the effects of estrone and estradiol and each hECFC function was analyzed. The extent to which estrone was similar in effect to that of estradiol was dependent on both the concentrations of estradiol and estrone and the hECFC function measured. Interestingly, when the two estrogens were present, differing ratios resulted in unique functional responses. hECFCs that were treated with combinations of estrone and estradiol with high estrone to estradiol ratios showed decreased proliferative capacity. Conversely, hECFCs that were treated with combinations that were relatively high in estradiol, showed increased proliferative capacity. Cells that were treated with estrone and estradiol in equal concentrations showed an attenuated proliferative response that was decreased compared to the proliferation that either estrone or estradiol produced when they were present alone. This co-inhibitory relationship, which has not been previously reported, challenges the prevailing understanding of estrone as solely a weak agonist at estrogen receptors. This study provides evidence that estrone signaling is distinct from that of estradiol and that further investigation of estrone\u27s mechanism of action and the biological effect may provide important insight into understanding the dysfunction and decreased number of hECFCs, and the resulting cardiovascular disease risk observed clinically in menopausal women and women undergoing hormone replacement therapy

Gender-Specific Protection from Microvessel Rarefaction in Female Hypertensive Rats

Epidemiologic studies reveal that women have a significantly lower age-adjusted morbidity and mortality from cardiovascular disease than men, suggesting that gender is a cardiovascular disease risk factor. The mechanism of the “gender protection” is unknown. In this study, we investigated the microvascular remodeling in reduced renal mass plus a high salt (4.0% NaCl) diet model of hypertension (RRM + HS). We hypothesized that women would be protected from the increase in blood pressure and from the microvascular rarefaction associated with RRM + HS hypertension. Studies were designed to determine whether female rats were less susceptible to changes in microvessel density during RRM + HS. Microvessel density was measured in male and female low salt (0.4% LS) sham-operated controls (Sham + LS) and after 3 days or 4 weeks of RRM + HS hypertension. The microcirculation of hind limb (medial and lateral gastrocnemius, plantaris, soleus) muscles was visualized using rhodamine-labeled Griffonia simplicifolia I lectin. Tissue sections were examined by videomicroscopy and microvessel density was determined by quantitative stereology. As shown previously, mean arterial pressure increased to 160 ± 8 mm Hg and microvessel density decreased (\u3e30% decrease in all beds) in male RRM + HS. In contrast, mean arterial pressure of female RRM + HS rats was modestly increased from 101 ± 2 to 118 ± 4 mm Hg. Despite previous results showing a reduction in microvessel density of both normotensive and hypertensive male rats on a high salt diet, microvessel density of female RRM + HS rats was not reduced at either time. These results suggest that gender protection in the RRM rat extends beyond an attenuation of the increase in pressure to an immunity from microvascular rarefaction

Computational Model of Vascular Endothelial Growth Factor Spatial Distribution in Muscle and Pro-Angiogenic Cell Therapy

Members of the vascular endothelial growth factor (VEGF) family of proteins are critical regulators of angiogenesis. VEGF concentration gradients are important for activation and chemotactic guidance of capillary sprouting, but measurement of these gradients in vivo is not currently possible. We have constructed a biophysically and molecularly detailed computational model to study microenvironmental transport of two isoforms of VEGF in rat extensor digitorum longus skeletal muscle under in vivo conditions. Using parameters based on experimental measurements, the model includes: VEGF secretion from muscle fibers; binding to the extracellular matrix; binding to and activation of endothelial cell surface VEGF receptors; and internalization. For 2-D cross sections of tissue, we analyzed predicted VEGF distributions, gradients, and receptor binding. Significant VEGF gradients (up to 12% change in VEGF concentration over 10 μm) were predicted in resting skeletal muscle with uniform VEGF secretion, due to non-uniform capillary distribution. These relative VEGF gradients were not sensitive to extracellular matrix composition, or to the overall VEGF expression level, but were dependent on VEGF receptor density and affinity, and internalization rate parameters. VEGF upregulation in a subset of fibers increased VEGF gradients, simulating transplantation of pro-angiogenic myoblasts, a possible therapy for ischemic diseases. The number and relative position of overexpressing fibers determined the VEGF gradients and distribution of VEGF receptor activation. With total VEGF expression level in the tissue unchanged, concentrating overexpression into a small number of adjacent fibers can increase the number of capillaries activated. The VEGF concentration gradients predicted for resting muscle (average 3% VEGF/10 μm) is sufficient for cellular sensing; the tip cell of a vessel sprout is approximately 50 μm long. The VEGF gradients also result in heterogeneity in the activation of blood vessel VEGF receptors. This first model of VEGF tissue transport and heterogeneity provides a platform for the design and evaluation of therapeutic approaches

Tissue-specific network-based genome wide study of amygdala imaging phenotypes to identify functional interaction modules

Motivation: Network-based genome-wide association studies (GWAS) aim to identify functional modules from biological networks that are enriched by top GWAS findings. Although gene functions are relevant to tissue context, most existing methods analyze tissue-free networks without reflecting phenotypic specificity. Results: We propose a novel module identification framework for imaging genetic studies using the tissue-specific functional interaction network. Our method includes three steps: (i) re-prioritize imaging GWAS findings by applying machine learning methods to incorporate network topological information and enhance the connectivity among top genes; (ii) detect densely connected modules based on interactions among top re-prioritized genes; and (iii) identify phenotype-relevant modules enriched by top GWAS findings. We demonstrate our method on the GWAS of [18F]FDG-PET measures in the amygdala region using the imaging genetic data from the Alzheimer's Disease Neuroimaging Initiative, and map the GWAS results onto the amygdala-specific functional interaction network. The proposed network-based GWAS method can effectively detect densely connected modules enriched by top GWAS findings. Tissue-specific functional network can provide precise context to help explore the collective effects of genes with biologically meaningful interactions specific to the studied phenotype

A detailed geochemical study of island arc crust : the Talkeetna Arc section, south–central Alaska

Author Posting. © The Author, 2006. This is the author's version of the work. It is posted here by permission of Oxford University Press for personal use, not for redistribution. The definitive version was published in Journal of Petrology 47 (2006): 1051-1093, doi:10.1093/petrology/egl002.The Early to Middle Jurassic Talkeetna Arc section exposed in the Chugach Mountains of south central Alaska is 5-18 km wide and extends for over 150 km. This accreted island arc includes exposures of upper mantle to volcanic upper crust. The section comprises six lithologic units, in order of decreasing depth: (1) residual upper mantle harzburgite (with lesser proportions of dunite); (2) pyroxenite; (3) basal gabbronorite; (4) lower crustal gabbronorite; (5) mid-crustal plutonic rocks; and (6) volcanic rocks. The pyroxenites overlie residual mantle peridotite, with some interfingering of the two along the contact. The basal gabbronorite overlies pyroxenite, again with some interfingering of the two different units along their contact. Lower crustal gabbronorite (≤10 km thick) includes abundant rocks with well developed modal layering. The mid-crustal plutonic rocks include a heterogeneous assemblage of gabbroic rocks, dioritic to tonalitic rocks (30-40% area), and concentrations of mafic dikes and chilled mafic inclusions. The volcanic rocks (~7 km thick) range from basalt to rhyolite. Many of the evolved volcanic compositions are a result of fractional crystallisation processes whose cumulate products are directly observable in the lower crustal gabbronorites. For example, Ti and Eu enrichments in lower crustal gabbronorites are mirrored by Ti and Eu depletions in evolved volcanics. In addition, calculated parental liquids from ion microprobe analyses of clinopyroxene in lower crustal gabbronorites indicate that the clinopyroxenes crystallised in equilibrium with liquids whose compositions were the same as the compositions of volcanic rocks. The compositional variation of the main series of volcanic and chilled mafic rocks can be modeled through fractionation of observed phase compositions and phase proportions in lower crustal gabbronorite (i.e. cumulates). Primary, mantle-derived melts in the Talkeetna Arc underwent fractionation of pyroxenite at the base of the crust. Our calculations suggest that more than 25 wt % of the primary melts crystallised as pyroxenites at the base of the crust. The discrepancy between the observed proportion of pyroxenites (less than 5% of the arc section) and the proportion required by crystal fractionation modeling (more than 25%) may be best understood as the result of gravitational instability, with dense ultramafic cumulates, probably together with dense garnet granulites, foundering into the underlying mantle during the time when the Talkeetna Arc was magmatically active, or in the initial phases of slow cooling (and sub-solidus garnet growth) immediately after the cessation of arc activity.This study was supported by National Science Foundation Grant EAR-9910899

Prescription drug monitoring program data tracking of opioid addiction treatment outcomes in integrated dual diagnosis care involving injectable naltrexone

BACKGROUND AND OBJECTIVES: Fourfold increases in opioid prescribing and dispensations over 2 decades in the U.S. has paralleled increases in opioid addictions and overdoses, requiring new preventative, diagnostic, and treatment strategies. This study examines Prescription Drug Monitoring Program (PDMP) tracking as a novel measure of opioid addiction treatment outcomes in a university-affiliated integrated mental health-addiction treatment clinic. METHODS: Repeated measure parametrics examined PDMP and urine drug screening (UDS) data before and after first injection for all patients (N = 68) who received at least one long-acting naltrexone injection (380 mg/IM) according to diagnostic groupings of having either (i) alcohol (control); (ii) opioid; or (iii) combined alcohol and opioid use disorders. RESULTS: There were no group differences post-injection in treatment days, injections delivered, or treatment service encounters. UDS and PDMP measures of opioid exposures were greater in opioid compared to alcohol-only patients. Post-first injection, UDS's positive for opioids declined (p < .05) along with PDMP measures of opioid prescriptions (p < .001), doses (p < .01), types (p < .001), numbers of dispensing prescribers (p < .001) and pharmacies (p < .001). Opioid patients without alcohol disorders showed the best outcomes with 50% to 80% reductions in PDMP-measures of opioids, down to levels of alcohol-only patients. CONCLUSIONS: This study shows PDMP utility for measuring opioid addiction treatment outcomes, supporting the routine use of PDMPs in clinical and research settings. SCIENTIFIC SIGNIFICANCE: These findings demonstrate that opioid addiction in patients with complex addictions and mental illnesses comorbidities can show effective treatment responses as measured by PDMP tracking of decreases in opioid prescriptions to those patients. (Am J Addict 2016;25:557-564)

ZoomQuant: An application for the quantitation of stable isotope labeled peptides

The main goal of comparative proteomics is the quantitation of the differences in abundance of many proteins between two different biological samples in a single experiment. By differentially labeling the peptides from the two samples and combining them in a single analysis, relative ratios of protein abundance can be accurately determined. Protease catalyzed 18O exchange is a simple method to differentially label peptides, but the lack of robust software tools to analyze the data from mass spectra of 18O labeled peptides generated by common ion trap mass spectrometers has been a limitation. ZoomQuant is a stand-alone computational tool that analyzes the mass spectra of 18O labeled peptides from ion trap instruments and determines relative abundance ratios between two samples. Starting with a filtered list of candidate peptides that have been successfully identified by Sequest, ZoomQuant analyzes the isotopic forms of the peptides using high-resolution zoom scan spectrum data. The theoretical isotope distribution is determined from the peptide sequence and is used to deconvolute the peak areas associated with the unlabeled, partially labeled, and fully labeled species. The ratio between the labeled and unlabeled peptides is then calculated using several different methods. ZoomQuant’s graphical user interface allows the user to view and adjust the parameters for peak calling and quantitation and select which peptides should contribute to the overall abundance ratio calculation. Finally, ZoomQuant generates a summary report of the relative abundance of the peptides identified in the two samples

Gravitating Instantons In 3 Dimensions

We study the Einstein-Chern-Simons gravity coupled to Yang-Mills-Higgs theory in three dimensional Euclidean space with cosmological constant. The classical equations reduce to Bogomol'nyi type first order equations in curved space. There are BPS type gauge theory instanton (monopole) solutions of finite action in a gravitational instanton which itself has a finite action. We also discuss gauge theory instantons in the vacuum (zero action) AdS space. In addition we point out to some exact solutions which are singular.Comment: 17 pages, 4 figures, title has changed, gravitational instanton actions are adde