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1.  Neighborhood Physical Disorder in New York City 
Journal of maps  2014;12(1):53-60.
Neighborhood physical disorder, or the deterioration of urban environments, is associated with negative mental and physical health outcomes. Eleven trained raters used CANVAS, a web-based system for conducting reliable virtual street audits, to collect data on nine indicators of physical disorder using Google Street View imagery of 532 block faces in New York City, New York, USA. We combined the block face indicator data into a disorder scale using item response theory; indicators ranged in severity from presence of litter, a weak indicator of disorder, to abandoned cars, a strong indicator. Using this scale, we estimated disorder at the center point of each sampled block. We then used ordinary kriging to interpolate estimates of disorder levels throughout the city. The resulting map condenses a complex estimation process into an interpretable visualization of the spatial distribution of physical disorder in New York City.
PMCID: PMC4963033  PMID: 27482283
2.  Rats overexpressing the dopamine transporter display behavioral and neurobiological abnormalities with relevance to repetitive disorders 
Scientific Reports  2016;6:39145.
The dopamine transporter (DAT) plays a pivotal role in maintaining optimal dopamine signaling. DAT-overactivity has been linked to various neuropsychiatric disorders yet so far the direct pathological consequences of it has not been fully assessed. We here generated a transgenic rat model that via pronuclear microinjection overexpresses the DAT gene. Our results demonstrate that DAT-overexpression induces multiple neurobiological effects that exceeded the expected alterations in the corticostriatal dopamine system. Furthermore, transgenic rats specifically exhibited behavioral and pharmaco-therapeutic profiles phenotypic of repetitive disorders. Together our findings suggest that the DAT rat model will constitute a valuable tool for further investigations into the pathological influence of DAT overexpression on neural systems relevant to neuropsychiatric disorders.
PMCID: PMC5156927  PMID: 27974817
3.  Importin-α7 Is Involved in the Formation of Ebola Virus Inclusion Bodies but Is Not Essential for Pathogenicity in Mice 
The Journal of Infectious Diseases  2015;212(Suppl 2):S316-S321.
Ebola virus (EBOV) protein 24 antagonizes the host interferon (IFN) response by hijacking select nuclear importin-α isoforms. Thereby, it blocks STAT1-mediated IFN-α/β and IFN-γ synthesis. However, owing to the lack of importin-α knockout animal models in the past, their role in EBOV pathogenesis remained largely unknown. Here, we demonstrate that importin-α7 is involved in the formation of EBOV inclusion bodies and replication. However, deletion of the gene encoding importin-α7 was not sufficient to increase survival rates among mice infected with EBOV.
PMCID: PMC4564549  PMID: 26185094
Ebola virus; importin-α; inclusion bodies; pathogenicity; VP24; interferon; STAT1
4.  Neprilysin is a Mediator of Alternative Renin-Angiotensin-System Activation in the Murine and Human Kidney 
Scientific Reports  2016;6:33678.
Cardiovascular and renal pathologies are frequently associated with an activated renin-angiotensin-system (RAS) and increased levels of its main effector and vasoconstrictor hormone angiotensin II (Ang II). Angiotensin-converting-enzyme-2 (ACE2) has been described as a crucial enzymatic player in shifting the RAS towards its so-called alternative vasodilative and reno-protective axis by enzymatically converting Ang II to angiotensin-(1-7) (Ang-(1-7)). Yet, the relative contribution of ACE2 to Ang-(1-7) formation in vivo has not been elucidated. Mass spectrometry based quantification of angiotensin metabolites in the kidney and plasma of ACE2 KO mice surprisingly revealed an increase in Ang-(1-7), suggesting additional pathways to be responsible for alternative RAS activation in vivo. Following assessment of angiotensin metabolism in kidney homogenates, we identified neprilysin (NEP) to be a major source of renal Ang-(1-7) in mice and humans. These findings were supported by MALDI imaging, showing NEP mediated Ang-(1-7) formation in whole kidney cryo-sections in mice. Finally, pharmacologic inhibition of NEP resulted in strongly decreased Ang-(1-7) levels in murine kidneys. This unexpected new role of NEP may have implications for the combination therapy with NEP-inhibitors and angiotensin-receptor-blockade, which has been shown being a promising therapeutic approach for heart failure therapy.
PMCID: PMC5030486  PMID: 27649628
5.  The caffeine-binding adenosine A2A receptor induces age-like HPA-axis dysfunction by targeting glucocorticoid receptor function 
Scientific Reports  2016;6:31493.
Caffeine is associated with procognitive effects in humans by counteracting overactivation of the adenosine A2A receptor (A2AR), which is upregulated in the human forebrain of aged and Alzheimer’s disease (AD) patients. We have previously shown that an anti-A2AR therapy reverts age-like memory deficits, by reestablishment of the hypothalamic-pituitary-adrenal (HPA) axis feedback and corticosterone circadian levels. These observations suggest that A2AR over-activation and glucocorticoid dysfunction are key events in age-related hippocampal deficits; but their direct connection has never been explored. We now show that inducing A2AR overexpression in an aging-like profile is sufficient to trigger HPA-axis dysfunction, namely loss of plasmatic corticosterone circadian oscillation, and promotes reduction of GR hippocampal levels. The synaptic plasticity and memory deficits triggered by GR in the hippocampus are amplified by A2AR over-activation and were rescued by anti-A2AR therapy; finally, we demonstrate that A2AR act on GR nuclear translocation and GR-dependent transcriptional regulation. We provide the first demonstration that A2AR is a major regulator of GR function and that this functional interconnection may be a trigger to age-related memory deficits. This supports the idea that the procognitive effects of A2AR antagonists, namely caffeine, on Alzheimer’s and age-related cognitive impairments may rely on its ability to modulate GR actions.
PMCID: PMC4980603  PMID: 27510168
6.  C-type natriuretic peptide and natriuretic peptide receptor B signalling inhibits cardiac sympathetic neurotransmission and autonomic function 
Cardiovascular Research  2016;112(3):637-644.
B-type natriuretic peptide (BNP)–natriuretic peptide receptor A (NPR-A) receptor signalling inhibits cardiac sympathetic neurotransmission, although C-type natriuretic peptide (CNP) is the predominant neuropeptide of the nervous system with expression in the heart and vasculature. We hypothesized that CNP acts similarly to BNP, and that transgenic rats (TGRs) with neuron-specific overexpression of a dominant negative NPR-B receptor would develop heightened sympathetic drive.
Methods and results
Mean arterial pressure and heart rate (HR) were significantly (P < 0.05) elevated in freely moving TGRs (n = 9) compared with Sprague Dawley (SD) controls (n = 10). TGR had impaired left ventricular systolic function and spectral analysis of HR variability suggested a shift towards sympathoexcitation. Immunohistochemistry demonstrated co-staining of NPR-B with tyrosine hydroxylase in stellate ganglia neurons. In SD rats, CNP (250 nM, n = 8) significantly reduced the tachycardia during right stellate ganglion stimulation (1–7 Hz) in vitro whereas the response to bath-applied norepinephrine (NE, 1 μM, n = 6) remained intact. CNP (250 nM, n = 8) significantly reduced the release of 3H-NE in isolated atria and this was prevented by the NPR-B antagonist P19 (250 nM, n = 6). The neuronal Ca2+ current (n = 6) and intracellular Ca2+ transient (n = 9, using fura-2AM) were also reduced by CNP in isolated stellate neurons. Treatment of the TGR (n = 9) with the sympatholytic clonidine (125 µg/kg per day) significantly reduced mean arterial pressure and HR to levels observed in the SD (n = 9).
C-type natriuretic peptide reduces cardiac sympathetic neurotransmission via a reduction in neuronal calcium signalling and NE release through the NPR-B receptor. Situations impairing CNP–NPR-B signalling lead to hypertension, tachycardia, and impaired left ventricular systolic function secondary to sympatho-excitation.
PMCID: PMC5157132  PMID: 27496871
Natriuretic peptides; Sympathetic; Norepinephrine; Calcium; Hypertension
7.  Lack of weight gain after angiotensin AT1 receptor blockade in diet-induced obesity is partly mediated by an angiotensin-(1–7)/ Mas-dependent pathway 
British Journal of Pharmacology  2015;172(15):3764-3778.
Background and Purpose
Angiotensin AT1 receptor antagonists induce weight loss; however, the mechanism underlying this phenomenon is unknown. The Mas receptor agonist angiotensin-(1-7) is a metabolite of angiotensin I and of angiotensin II. As an agonist of Mas receptors, angiotensin-(1-7) has beneficial cardiovascular and metabolic effects.
Experimental Approach
We investigated the anti-obesity effects of transgenically overexpressed angiotensin-(1-7) in rats. We secondly examined whether weight loss due to telmisartan (8 mg·kg−1·d−1) in diet-induced obese Sprague Dawley (SD) rats can be blocked when the animals were co-treated with the Mas receptor antagonist A779 (24 or 72 μg·kg−1·d−1).
Key Results
In contrast to wild-type controls, transgenic rats overexpressing angiotensin-(1-7) had 1.) diminished body weight when they were regularly fed with chow; 2.) were protected from developing obesity although they were fed with cafeteria diet (CD); 3.) showed a reduced energy intake that was mainly related to a lower CD intake; 5.) remained responsive to leptin despite chronic CD feeding; 6.) had a higher, strain-dependent energy expenditure, and 7.) were protected from developing insulin resistance despite CD feeding. Telmisartan-induced weight loss in SD rats was partially antagonized after a high, but not a low dose of A779.
Conclusions and Implications
Angiotensin-(1-7) regulated food intake and body weight and contributed to the weight loss after AT1 receptor blockade. Angiotensin-(1-7)-like agonists may be drug candidates for treating obesity.
PMCID: PMC4523334  PMID: 25906670
8.  Activation of kinin receptor B1 limits encephalitogenic T lymphocyte recruitment to the central nervous system 
Nature medicine  2009;15(7):788-793.
Previous proteomic and transcriptional analyses of multiple sclerosis lesions1, 2, 3 revealed modulation of the renin-angiotensin and the opposing kallikrein-kinin pathways. Here we identify kinin receptor B1 (Bdkrb1) as a specific modulator of immune cell entry into the central nervous system (CNS). We demonstrate that the Bdkrb1 agonist R838 (Sar-[d-Phe]des-Arg9-bradykinin) markedly decreases the clinical symptoms of experimental autoimmune encephalomyelitis (EAE) in SJL mice4, 5, 6, whereas the Bdkrb1 antagonist R715 (Ac-Lys-[d-βNal7, Ile8]des-Arg9-bradykinin) resulted in earlier onset and greater severity of the disease. Bdkrb1-deficient (Bdkrb1−/−) C57BL/6 mice7 immunized with a myelin oligodendrocyte glycoprotein fragment, MOG35–55, showed more severe disease with enhanced CNS-immune cell infiltration. The same held true for mixed bone marrow–chimeric mice reconstituted with Bdkrb1−/− T lymphocytes, which showed enhanced T helper type 17 (TH17) cell invasion into the CNS. Pharmacological modulation of Bdkrb1 revealed that in vitro migration of human TH17 lymphocytes across blood-brain barrier endothelium is regulated by this receptor. Taken together, these results suggest that the kallikrein-kinin system is involved in the regulation of CNS inflammation, limiting encephalitogenic T lymphocyte infiltration into the CNS, and provide evidence that Bdkrb1 could be a new target for the treatment of chronic inflammatory diseases such as multiple sclerosis.
PMCID: PMC4903020  PMID: 19561616
9.  Angiotensin-(1-7) attenuates disuse skeletal muscle atrophy in mice via its receptor, Mas 
Disease Models & Mechanisms  2016;9(4):441-449.
Immobilization is a form of disuse characterized by a loss of strength and muscle mass. Among the main features are decreased IGF-1/Akt signalling and increased ubiquitin-proteasome pathway signalling, which induce greater myosin heavy chain degradation. Activation of the classical renin-angiotensin system (RAS) causes deleterious effects in skeletal muscle, including muscle wasting. In contrast, angiotensin-(1-7) [Ang-(1-7)], a peptide of the non-classical RAS, produces beneficial effects in skeletal muscle. However, the role of Ang-(1-7) in skeletal muscle disuse atrophy and independent of classical RAS activation has not been evaluated. Therefore, we assessed the functions of Ang-(1-7) and the Mas receptor in disuse muscle atrophy in vivo using unilateral cast immobilization of the hind limb in male, 12-week-old wild-type (WT) and Mas-knockout (Mas KO) mice for 1 and 14 days. Additionally, we evaluated the participation of IGF-1/IGFR-1/Akt signalling and ubiquitin-proteasome pathway expression on the effects of Ang-(1-7) immobilization-induced muscle atrophy. Our results found that Ang-(1-7) prevented decreased muscle strength and reduced myofiber diameter, myosin heavy chain levels, and the induction of atrogin-1 and MuRF-1 expressions, all of which normally occur during immobilization. Analyses indicated that Ang-(1-7) increases IGF-1/IGFR-1/Akt pathway signalling through IGFR-1 and Akt phosphorylation, and the concomitant activation of two downstream targets of Akt, p70S6K and FoxO3. These anti-atrophic effects of Ang-(1-7) were not observed in Mas KO mice, indicating crucial participation of the Mas receptor. This report is the first to propose anti-atrophic effects of Ang-(1-7) via the Mas receptor and the participation of the IGF-1/IGFR-1/Akt/p70S6K/FoxO3 mechanism in disuse skeletal muscle atrophy.
Summary: In this article, the authors demonstrate that a peptide with actions mainly in the cardiovascular system prevents the skeletal muscle damage induced by disuse.
PMCID: PMC4852504  PMID: 26851244
Disuse; Angiotensin-(1-7); Mas receptor; Skeletal muscle; Atrophy
10.  Stable maintenance of de novo assembled human artificial chromosomes in embryonic stem cells and their differentiated progeny in mice 
Cell Cycle  2015;14(8):1268-1273.
De novo assembled alphoidtetO-type human artificial chromosomes (HACs) represent a novel promising generation of high capacity episomal vectors. Their function and persistence, and any adverse effects, in various cell types in live animals, have not, however, been explored. In this study we transferred the alphoidtetO-HAC into mouse ES cells and assessed whether the presence of this extra chromosome affects their pluripotent properties. AlphoidtetO-HAC-bearing ES cells were indistinguishable from their wild-type counterparts: they retained self-renewal potential and full capacity for multilineage differentiation during mouse development, whereas the HAC itself was mitotically and transcriptionally stable during this process. Our data provide the first example of fully synthetic DNA behaving like a normal chromosome in cells of living animals. It also opens a new perspective into functional genetic studies in laboratory animals as well as stem cell-based regenerative medicine.
PMCID: PMC4614155  PMID: 25695642
embryonic stem cells; human artificial chromosomes; gene therapy
11.  Normothermic Mouse Functional MRI of Acute Focal Thermostimulation for Probing Nociception 
Scientific Reports  2016;6:17230.
Combining mouse genomics and functional magnetic resonance imaging (fMRI) provides a promising tool to unravel the molecular mechanisms of chronic pain. Probing murine nociception via the blood oxygenation level-dependent (BOLD) effect is still challenging due to methodological constraints. Here we report on the reproducible application of acute noxious heat stimuli to examine the feasibility and limitations of functional brain mapping for central pain processing in mice. Recent technical and procedural advances were applied for enhanced BOLD signal detection and a tight control of physiological parameters. The latter includes the development of a novel mouse cradle designed to maintain whole-body normothermia in anesthetized mice during fMRI in a way that reflects the thermal status of awake, resting mice. Applying mild noxious heat stimuli to wildtype mice resulted in highly significant BOLD patterns in anatomical brain structures forming the pain matrix, which comprise temporal signal intensity changes of up to 6% magnitude. We also observed sub-threshold correlation patterns in large areas of the brain, as well as alterations in mean arterial blood pressure (MABP) in response to the applied stimulus.
PMCID: PMC4731789  PMID: 26821826
12.  Development and Deployment of the Computer Assisted Neighborhood Visual Assessment System (CANVAS) to Measure Health-Related Neighborhood Conditions 
Health & place  2014;31:163-172.
Public health research has shown that neighborhood conditions are associated with health behaviors and outcomes. Systematic neighborhood audits have helped researchers measure neighborhood conditions that they deem theoretically relevant but not available in existing administrative data. Systematic audits, however, are expensive to conduct and rarely comparable across geographic regions. We describe the development of an online application, the Computer Assisted Neighborhood Visual Assessment System (CANVAS), that uses Google Street View to conduct virtual audits of neighborhood environments. We use this system to assess the inter-rater reliability of 187 items related to walkability and physical disorder on a national sample of 150 street segments in the United States. We find that many items are reliably measured across auditors using CANVAS and that agreement between auditors appears to be uncorrelated with neighborhood demographic characteristics. Based on our results we conclude that Google Street View and CANVAS offer opportunities to develop greater comparability across neighborhood audit studies.
PMCID: PMC4315325  PMID: 25545769
Neighborhood; walkability; disorder; measurement error; neighborhood audit; systematic social observation; Google Street View
13.  Maternal Forced Swimming Reduces Cell Proliferation in the Postnatal Dentate Gyrus of Mouse Offspring 
Physical exercise positively affects the metabolism and induces proliferation of precursor cells in the adult brain. Maternal exercise likewise provokes adaptations early in the offspring. Using a high-intensity swimming protocol that comprises forced swim training before and during pregnancy, we determined the effect of maternal swimming on the mouse offspring's neurogenesis. Our data demonstrate decreased proliferation in sublayers of the postnatal dentate gyrus in offspring of swimming mother at postnatal day (P) 8 accompanied with decreased survival of newly generated cells 4 weeks later. The reduction in cell numbers was predominantly seen in the hilus and molecular layer. At P35, the reduced amount of cells was also reflected by a decrease in the population of newly generated immature and mature neurons of the granule cell layer. Our data suggest that forced maternal swimming at high-intensity has a negative effect on the neurogenic niche development in postnatal offspring.
PMCID: PMC5002407  PMID: 27621701
exercise; neurogenesis; BrdU; pregnancy; hippocampus
14.  Effect of Angiotensin(1-7) on Heart Function in an Experimental Rat Model of Obesity 
Aim: Obesity is a risk factor for the development of cardiovascular diseases. Recently it was shown that overexpression of the Mas-receptor antagonist angiotensin(1-7) could prevent from diet-induced obesity. However, it remained unclear whether diet-induced obesity and angiotensin(1-7) overexpression might also have effects on the cardiovascular system in these rats.
Methods:Twenty three male Sprague Dawley rats were fed with standard chow (SD+chow, n = 5) or a cafeteria diet (SD+CD, n = 6) for 5 months. To investigate the effect of angiotensin(1-7) transgenic rats, expressing an angiotensin(1-7)-producing fusion protein in testis were used. These transgenic rats also received a 5 month's feeding period with either chow (TGR+chow, n = 6) or cafeteria diet (TGR+CD, n = 6), respectively. Hemodynamic measurements (pressure-volume loops) were carried out to assess cardiac function and blood pressure. Subsequently, hearts were explanted and investigated according to the Langendorff technique. Furthermore, cardiac remodeling in these animals was investigated histologically.
Results:After 5 months cafeteria diet feeding rats showed a significantly increased body weight, which could be prevented in transgenic rats. However, there was no effect on cardiac performance after cafeteria diet in non-transgenic and transgenic rats. Moreover, overexpression of angiotensin(1-7) deteriorated cardiac contractility as indicated by impaired dp/dt. Furthermore, histological analysis revealed that cafeteria diet led to myocardial fibrosis in both, control and transgenic rats and this was not inhibited by an overproduction of angiotensin(1-7).
Conclusion:These results indicate that an overexpression of circulating angiotensin(1-7) prevents a cafeteria diet-induced increase in body weight, but does not affect cardiac performance in this experimental rat model of obesity. Furthermore, overexpression of angiotensin(1-7) alone resulted in an impairment of cardiac function.
PMCID: PMC4685089  PMID: 26733884
angiotensin(1-7); cafeteria diet; heart; obesity; transgenic rats
15.  Role of the B1 Kinin Receptor in the Regulation of Cardiac Function and Remodeling After Myocardial Infarction 
Hypertension  2005;45(4):747-753.
Kinins exert cardioprotective effects via 2 G-protein-coupled receptors, B1 and B2. Using B1 kinin receptor gene knockout mice (B1 −/−), we tested the hypotheses that the B1 receptor plays an important role in preservation of cardiac function, whereas lack of B1 may accelerate cardiac remodeling and dysfunction after myocardial infarction, and that B2 receptors may compensate for lack of B1, whereas blockade of B2 receptors in B1 −/− mice may cause further deterioration of cardiac function and remodeling. Female B1 −/− mice and wild-type controls (C57BL/6J, B1 +/+) underwent sham surgery or myocardial infarction and were treated with either vehicle or B2-antagonist (icatibant, 500 μg/kg per day, subcutaneous) for 8 weeks. We found that in sham myocardial infarction, B1 −/− mice had a larger left ventricular diastolic chamber dimension both initially and at 4 to 8 weeks compared with B1 +/+. Left ventricular mass and myocyte size were also larger in B1 −/− with sham operation than in B1 +/+, although cardiac function did not differ between strains. After myocardial infarction, cardiac remodeling and function were similar in both strains, although B1 −/− mice tended to have lower blood pressure. Blockade of B2 receptors tended to worsen cardiac remodeling and dysfunction in B1 −/− but not in B1 +/+. These results may suggest that B2 receptors play an important role in compensating for lack of B1 receptors in mice with myocardial infarction. Dual blockade of both B1 and B2 eliminates this compensation, leading to further deterioration of cardiac dysfunction and remodeling after myocardial infarction.
PMCID: PMC4593484  PMID: 15699461
kinins; myocardial infarction; mice
16.  Measuring health-relevant businesses over 21 years: refining the National Establishment Time-Series (NETS), a dynamic longitudinal data set 
BMC Research Notes  2015;8:507.
The densities of food retailers, alcohol outlets, physical activity facilities, and medical facilities have been associated with diet, physical activity, and management of medical conditions. Most of the research, however, has relied on cross-sectional studies. In this paper, we assess methodological issues raised by a data source that is increasingly used to characterize change in the local business environment: the National Establishment Time Series (NETS) dataset.
Longitudinal data, such as NETS, offer opportunities to assess how differential access to resources impacts population health, to consider correlations among multiple environmental influences across the life course, and to gain a better understanding of their interactions and cumulative health effects. Longitudinal data also introduce new data management, geoprocessing, and business categorization challenges. Examining geocoding accuracy and categorization over 21 years of data in 23 counties surrounding New York City (NY, USA), we find that health-related business environments change considerably over time. We note that re-geocoding data may improve spatial precision, particularly in early years. Our intent with this paper is to make future public health applications of NETS data more efficient, since the size and complexity of the data can be difficult to exploit fully within its 2-year data-licensing period. Further, standardized approaches to NETS and other “big data” will facilitate the veracity and comparability of results across studies.
Electronic supplementary material
The online version of this article (doi:10.1186/s13104-015-1482-4) contains supplementary material, which is available to authorized users.
PMCID: PMC4588464  PMID: 26420471
Longitudinal data resource; GIS; Public health; Retail environment; Commercial businesses
17.  Validity of an Ecometric Neighborhood Physical Disorder Measure Constructed by Virtual Street Audit 
American Journal of Epidemiology  2014;180(6):626-635.
Neighborhood physical disorder is thought to affect mental and physical health, but it has been difficult to measure objectively and reliably across large geographical areas or multiple locales. Virtual street audits are a novel method for assessing neighborhood characteristics. We evaluated the ecometric properties of a neighborhood physical disorder measure constructed from virtual street audit data. Eleven trained auditors assessed 9 previously validated items developed to capture physical disorder (e.g., litter, graffiti, and abandoned buildings) on 1,826 block faces using Google Street View imagery (Google, Inc., Mountain View, California) dating from 2007–2011 in 4 US cities (San Jose, California; Detroit, Michigan; New York, New York; and Philadelphia, Pennsylvania). We constructed a 2-parameter item response theory scale to estimate latent levels of disorder on each block face and defined a function using kriging to estimate physical disorder levels, with confidence estimates, for any point in each city. The internal consistency reliability of the resulting scale was 0.93. The final measure of disorder was positively correlated with US Census data on unemployment and housing vacancy and negatively correlated with data on owner-occupied housing. These results suggest that neighborhood physical disorder can be measured reliably and validly using virtual audits, facilitating research on possible associations between physical disorder and health.
PMCID: PMC4157697  PMID: 25122584
cities; data collection; epidemiologic methods; psychometrics; residence characteristics; social environment; spatial analysis; urban health
18.  Increased Ang II Contraction of the Uterine Artery at Early Gestation in A Transgenic Model of Hypertensive Pregnancy is Reduced by Inhibition of Endocannabinoid Hydrolysis 
Hypertension  2014;64(3):619-625.
Increased vascular sensitivity to Ang II is a marker of a hypertensive human pregnancy. Recent evidence of interactions between the RAS and the endocannabinoid system (ECS) suggests that anandamide (AEA) and 2-arachidonoylglycerol (2-AG) may modulate Ang II contraction. We hypothesized that these interactions may contribute to the enhanced vascular responses in hypertensive pregnancy. We studied Ang II contraction in isolated uterine artery (UA) at early gestation in a rat model that mimics many features of preeclampsia, the transgenic hAGN×hREN (TgA), and control Sprague-Dawley (SD) rats. We determined the role of the cannabinoid receptor CB1 by blockade with SR171416A, and the contribution of AEA and 2-AG degradation to Ang II contraction by inhibiting their hydrolyzing enzymes FAAH (with URB597) or MAGL (with JZL184) respectively. TgA UA showed increased maximal contraction and sensitivity to Ang II that was inhibited by indomethacin. FAAH blockade decreased Ang IIMAX in SD UA, and decreased both Ang IIMAX and sensitivity in TgA UA. MAGL blockade had no effect on SD UA and decreased Ang IIMAX and sensitivity in TgA UA. Blockade of the CB1 receptor in TgA UA had no effect. Immunolocalization of FAAH and MAGL showed a similar pattern between groups; FAAH predominantly localized in endothelium and MAGL in smooth muscle cells. We demonstrated an increased Ang II contraction in TgA UA before initiation of the hypertensive phenotype. AEA and 2-AG reduced Ang II contraction in a CB1-independent manner. These RAS-ECS interactions may contribute to the enhanced vascular reactivity in early stages of hypertensive pregnancy.
PMCID: PMC4134408  PMID: 24935942
hypertensive pregnancy; endocannabinoids; Ang II; FAAH; MAGL
19.  Kinin B1 and B2 receptor deficiency protects against obesity induced by a high-fat diet and improves glucose tolerance in mice 
The kallikrein-kinin system is well known for its role in pain and inflammation, and has been shown recently by our group to have a role also in the regulation of energy expenditure. We have demonstrated that B1 receptor knockout (B1KO) mice are resistant to obesity induced by a high-fat diet (HFD) and that B1 receptor expression in adipocytes regulates glucose tolerance and predisposition to obesity. However, it is also known that in the absence of B1 receptor, the B2 receptor is overexpressed and can take over the function of its B1 counterpart, rendering uncertain the role of each kinin receptor in these metabolic effects. Therefore, we investigated the impact of ablation of each kinin receptor on energy metabolism using double kinin receptor knockout (B1B2KO) mice. Our data show that B1B2KO mice were resistant to HFD-induced obesity, with lower food intake and feed efficiency when compared with wild-type mice. They also had lower blood insulin and leptin levels and higher glucose tolerance after treatment with an HFD. Gene expression for tumor necrosis factor-alpha and C-reactive protein, which are important genes for insulin resistance, was reduced in white adipose tissue, skeletal muscle, and the liver in B1B2KO mice after the HFD. In summary, our data show that disruption of kinin B1 and B2 receptors has a profound impact on metabolic homeostasis in mice, by improving glucose tolerance and preventing HFD-induced obesity. These novel findings could pave the way for development of new pharmacological strategies to treat metabolic disorders such as insulin resistance and obesity.
PMCID: PMC4554409  PMID: 26346752
kallikrein-kinin system; B1/B2 receptors; obesity; glucose tolerance; insulin resistance
20.  Deletion of Kinin B2 Receptor Alters Muscle Metabolism and Exercise Performance 
PLoS ONE  2015;10(8):e0134844.
Metabolic syndrome is a cluster of metabolic risk factors such as obesity, diabetes and cardiovascular diseases. Mitochondria is the main site of ATP production and its dysfunction leads to decreased oxidative phosphorylation, resulting in lipid accumulation and insulin resistance. Our group has demonstrated that kinins can modulate glucose and lipid metabolism as well as skeletal muscle mass. By using B2 receptor knockout mice (B2R-/-) we investigated whether kinin action affects weight gain and physical performance of the animals. Our results show that B2R-/- mice are resistant to high fat diet-induced obesity, have higher glucose tolerance as well as increased mitochondrial mass. These features are accompanied by higher energy expenditure and a lower feed efficiency associated with an increase in the proportion of type I fibers and intermediary fibers characterized by higher mitochondrial content and increased expression of genes related to oxidative metabolism. Additionally, the increased percentage of oxidative skeletal muscle fibers and mitochondrial apparatus in B2R-/- mice is coupled with a higher aerobic exercise performance. Taken together, our data give support to the involvement of kinins in skeletal muscle fiber type distribution and muscle metabolism, which ultimately protects against fat-induced obesity and improves aerobic exercise performance.
PMCID: PMC4547798  PMID: 26302153
21.  Angiotensin 1-7 Reduces Mortality and Rupture of Intracranial Aneurysms in Mice 
Hypertension  2014;64(2):362-368.
Angiotensin II (Ang-II) stimulates vascular inflammation, oxidative stress, and formation and rupture of intracranial aneurysms in mice. Because angiotensin 1-7 (Ang-1-7) acts on Mas receptors and generally counteracts deleterious effects of Ang-II, we tested the hypothesis that Ang-1-7 attenuates formation and rupture of intracranial aneurysms. Intracranial aneurysms were induced in wild type and Mas receptor deficient mice using a combination of Ang-II-induced hypertension and intracranial injection of elastase in the basal cistern. Mice received elastase+Ang-II alone, or a combination of elastase+Ang-II+Ang-1-7. Aneurysm formation, prevalence of subarachnoid hemorrhage, mortality, and expression of molecules involved in vascular injury were assessed. Systolic blood pressure was similar in mice receiving elastase+Ang-II (148±5 mmHg, mean ±SE) or elastase+Ang-II+Ang-1-7 (144±5 mmHg). Aneurysm formation was also similar in mice receiving elastase+Ang-II (89%) or elastase+Ang-II+Ang-1-7 (84%). However, in mice that received elastase and Ang II, Ang-1-7 reduced mortality (from 64 to 36%, p<0.05) and prevalence of subarachnoid hemorrhage (from 75 to 48%, p<0.05). In cerebral arteries, expression of the inflammatory markers, Nox2 and catalase increased similarly in elastase+Ang-II or elastase+Ang-II+Ang-1-7 groups. Ang-1-7 increased expression of cyclooxygenase-2, and decreased expression of metalloproteinase 9 induced by elastase+Ang-II (p<0.05). In Mas receptor deficient mice, systolic blood pressure, mortality, and prevalence of subarachnoid hemorrhage were similar (p>0.05) in groups treated with elastase+Ang-II or elastase+Ang-II+Ang-1-7. Expression of Mas receptor was detected by immunohistochemistry in samples of human intracranial arteries and aneurysms. In conclusion, without attenuating Ang-II-induced hypertension, Ang-1-7 decreased mortality and rupture of intracranial aneurysms in mice, through a Mas receptor-dependent pathway.
PMCID: PMC4096422  PMID: 24799613
Angiotensin-1-7; intracranial aneurysm; subarachnoid hemorrhage; Mas receptor; hypertension
22.  The Impact of Neighborhood Park Access and Quality on Body Mass Index Among Adults in New York City 
Preventive medicine  2014;64:63-68.
To evaluate the association between adult individuals’ body mass index (BMI) and characteristics of parks (size and cleanliness) in an urban environment taking into account the physical and social environment of the neighborhood.
Cross-sectional, hierarchical linear models were used to determine whether park effects were associated with BMI using self-reported height and weight data obtained from the Community Health Survey in New York City (2002-2006).
Both the proportion of the residential zip code that was large park space and the proportion that was small park space had significant inverse associations with BMI after controlling for individual socio-demographic and zip code built environment characteristics (-0.20 BMI units across the inter-quartile range (IQR) for large parks, 95% CI -0.32, -0.08; -0.21 BMI units across the IQR for small parks, 95% CI -0.31, -0.10, respectively). Poorer scores on the park cleanliness index were associated with higher BMI, 0.18 BMI units across the IQR of the park cleanliness index (95% CI 0.05, 0.30).
This study demonstrated that proportion of neighborhoods that was large or small park space and park cleanliness were associated with lower BMI among NYC adults after adjusting for other neighborhood features such as homicides and walkability, characteristics that could influence park usage.
PMCID: PMC4314092  PMID: 24704504
23.  Realizing Racial and Ethnic Neighborhood Preferences? Exploring the Mismatches Between What People Want, Where They Search, and Where They Live 
The housing search process is an overlooked mechanism in the scholarly research that seeks to understand the causes of persistent racial residential segregation in the United States. Past research has explored in detail the preferences people hold in terms of the racial and ethnic composition of their neighborhoods, and more recently some have also examined the correspondence between racial and ethnic neighborhood preferences and current neighborhood racial/ethnic composition. But an intermediate stage—the racial/ethnic composition of where people search—has not been investigated. We analyze a subsample (n = 382) from the 2004–2005 Chicago Area Study to demonstrate the value of systematically studying the matches—or mismatches—between preferences, search locations, and neighborhood outcomes. We find that for whites, not only their current neighborhoods but also the neighborhoods in which they search for housing have larger percentages of whites than they say they prefer. In contrast, blacks—and to a lesser extent Latinos—search in neighborhoods that correspond to their preferences, but reside in neighborhoods with a larger percentage own group. Logistic regression analyses reveal that mismatches are associated with both a lack of information and inadequate finances, but also may be due to socially desirable responding for whites in particular. Our results provide suggestive evidence of the importance of unpacking the search process more generally and draw attention to what are likely to be productive new future data collection efforts as well as an area potentially ripe for policy interventions.
PMCID: PMC4716051  PMID: 26806990
Racial residential preferences; Housing search; Residential segregation; Chicago
24.  Comparing nutrition environments in bodegas and fast food restaurants 
Many small grocery stores or “bodegas” sell prepared or ready-to-eat items, filling a similar niche in the food environment as fast food restaurants. However, little comparative information is available about the nutrition environments of bodegas and fast food outlets. This study compared the nutrition environments of bodegas and national chain fast food restaurants using a common audit instrument, the Nutrition Environment Measures Study in Restaurants (NEMS-R) protocol. The analytic sample included 109 bodegas and 107 fast food restaurants located in New York City neighborhoods in the upper third and lower third of the census tract poverty rate distribution. Inter-rater reliability was evaluated in 102 food outlets including 31 from the analytic sample and 71 from a supplementary convenience sample. The analysis compared scores on individual NEMS-R items, a total summary score, and sub-scores indicating healthy food availability, nutrition information, promotions of healthy or unhealthy eating, and price incentives for healthy eating, using t-tests and chi-square statistics to evaluate differences by outlet type and neighborhood poverty. Fast food restaurants were more likely to provide nutritional information, while bodegas scored higher on healthy food availability, promotions, and pricing. Bodegas and fast food restaurants had similar NEMS-R total scores (bodegas: 13.09, fast food: 14.31, p=0.22). NEMS-R total scores were higher (indicating healthier environments) in low- than high-poverty neighborhoods among both bodegas (14.79 vs. 11.54, p=0.01) and fast food restaurants (16.27 vs. 11.60, p<.01). Results imply different policy measures to improve nutrition environments in the two types of food outlets.
PMCID: PMC4465191  PMID: 24035459
nutrition environment; restaurants; NEMS-R; fast food; corner stores
25.  Measurement of plasma, serum, and platelet serotonin in individuals with high bone mass and mutations in LRP5 
It has recently been suggested that the low-density lipoprotein receptor-related protein 5 (LRP5) regulates bone mass by suppressing secretion of serotonin from duodenal enterochromaffin cells. In mice with targeted expression of a high bone mass-causing (HBM-causing) LRP5 mutation and in humans with HBM LRP5 mutations, circulating serotonin levels have been reported to be lower than in controls while individuals with loss-of-function mutations in LRP5 have high blood serotonin. In contrast, others have reported that conditionally activating a knock-in allele of an HBM-causing LRP5 mutation in several tissues, or genetic deletion of LRP5 in mice has no effect on serum serotonin levels. To further explore the possible association between HBM-causing LRP5 mutations and circulating serotonin, levels of the hormone were measured in the platelet poor plasma (PPP), serum, and platelet pellet (PP) of 16 affected individuals from 2 kindreds with HBM-causing LRP5 mutations (G171V and N198S) and 16 age-matched controls. When analyzed by HPLC, there were no differences in levels of serotonin in PPP and PP between affected individuals and age-matched controls. Similarly, when analyzed by ELISA, there were no differences in PPP or PP between these two groups. By ELISA, serum levels of serotonin were higher in the affected individuals when compared to age-matched controls. A subgroup analysis of only the G171V subjects (n=14) demonstrated that there were no differences in PPP and PP serotonin between affected individuals and controls when analyzed by HPLC. PP serotonin was lower in the affected individuals when measured by ELISA but serum serotonin levels were not different. We conclude that there is no change in PPP serotonin in individuals with HBM-causing mutations in LRP5.
PMCID: PMC3935983  PMID: 24038240
Wnt/Beta-catenin/LRPs; Osteoporosis; Other ; Osteoblasts; DXA

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