tbuckley/cabot-search huggingface dataset:
Abstract 5426: Identification of Selective Small Molecule Inhibitors of Vascular Endothelial Growth Factor (VEGF) and Bone Morphogenetic Protein (BMP) Signaling Using Zebrafish-based in vivo Structure Activity Relationship Studies
Authors: Jijun Hao, Joshua N Ho, Richard N Daniels, Kaleh A Karim, Clare K Murphy, Corey R Hopkins, Craig Lindsley, Charles C Hong
Journal: Circulation (2009)

Angiogenesis, a physiological process of forming new blood vessels from pre-existing ones, plays a vital role in organogenesis, tissue response to ischemia, and malignant tumor growth. Angiogenesis is a complex process, requiring a finely tuned balance between various stimulatory and inhibitory signals. Vascular endothelial growth factors (VEGFs) are a major class of proangiogenic mediators that fuction by binding and activating the VEGF receptor tyrosine kinases, including VEGFR2/KDR/Flk-1. Additionally, bone morphogenetic proteins (BMPs) play a critical role in modulating angiogenesis via cross talks between the BMP and VEGF signaling at variety of levels. We recently identified dorsomorphin, the first known small molecule BMP signaling inhibitor, based on its ability to perturb zebrafish embryonic dorsoventral axis, which is normally established by a BMP signaling gradient. Here we show that dorsomorphin can also disrupt angiogenic intersomitic vessel (ISV) formation and has significant off-target activity against the type-2 VEGF receptor (Flk1/KDR). To determine whether dorsomorphin’s anti-angiogenic effects in vivo are due to its effects on BMP, VEGF, or both signals, we conducted a structure activity relationship (SAR) studies of over 70 dorsomorphin analogs purely based on their in vivo effects on zebrafish embryos. We found that dorsomorphin analogs which caused embryonic dorsalization, but had no effect on ISV formation were potent BMP inhibitors but not VEGF/PDGF inhibitors. Conversely, analogs that disrupt angiogenesis but not dorsoventral axis were found to be potent VEGF inibitors, but not BMP inhibitors. These results show that BMP signaling is not required for ISV formation in zebrafish. Moreover, this effort has led to the identification of exquisitely selective BMP and KDR inhibitors with superior in vivo bioavailability and efficacy. To our knowledge, this is the first large-scale SAR study performed in whole animals, and demonstrate the potential of zebrafish chemical embryogenesis for drug development.
Abstract 5095: The Role of Circulating Transforming Growth Factor-β in Vascular Ehlers-Danlos Syndrome: Implications for Drug Therapy
Authors: Florian S Schoenhoff, Benjamin F Griswold, Peter Matt, Leslie J Sloper, Michiyo Yamazaki, Olga D Carlson, Harry C Dietz, Jennifer E Van Eyk, Nazli B McDonnell
Journal: Circulation (2009)

Objective: TGFβ signaling has been shown to play a major role in the pathogenesis of Marfan syndrome (MFS), leading to a novel treatment strategy through TGFβ inhibition using losartan. We hypothesized that circulating TGFβ levels may be elevated in disorders that disrupt arterial wall extracellular matrix, such as the vascular form of Ehlers-Danlos syndrome (VEDS). Patients and Methods: Circulating levels of TGFβ-1 were measured in EDTA plasma of 141 patients with MFS (n=21, mean age 43±16y), VEDS (n=41, 37±13y) and controls (n=79, 48±13y) using an electrochemoluminescence platform (LLOQ 4±2.6pg/ml). Results: In keeping with prior work, this study revealed increased circulating TGFβ in patients with MFS compared to control patients (9.2±1.2ng/ml vs. 2.5±0.4ng/ml, p&lt;0.0001). Remarkably, the levels seen in patients with VEDS were also significantly higher than controls (8.0±1.0ng/ml vs. 2.5±0.4ng/ml, p&lt;0.0001) and statistically indistinguishable from those seen in MFS (9.2±1.2ng/ml vs. 8.0±1.0ng/ml, p=0.5). In a bivariate logistic regression model, the odds ratio was 7.5 (p=0.02, CI 1.3– 43.3) when comparing quartiles of TGFβ values in VEDS patients with age, sex and BMI matched controls. There was a non-statistically significant trend for higher TGFβ levels in patients without cardiovascular medication (MFS, 11.4±3.0ng/ml; VEDS, 8.5±1.3ng/ml) compared to patients treated with ARBs and/or ACE-Is (MFS, 6.1±1.0ng/ml; VEDS, 4.6±0.8ng/ml), whereas β-blockers appeared to have some impact on TGFβ levels in MFS (9.0±1.7ng/ml) but not in VEDS patients (8.3±1.8ng/ml). The influence of age on TGFβ levels in the controls is statistically significant but weak (r=0.3, p=0.007). In the disease groups, TGFβ is inversely related to age (MFS, r=−0.7, p&lt;0.0001; VEDS, r=−0.1, p=0.6), which is most likely due to ascertainment bias towards a less severe phenotype in the older patients and longer duration of medical therapy, especially in the MFS population. Conclusion: Further investigation is warranted to establish the role of TGFβ signaling in the pathogenesis of VEDS. The current results may help to provide a rationale for the use of TGFβ lowering drug therapy in this patient population as it is emerging in the MFS patient population.
Abstract 5428: Nuclear Factor Kappa B Mediates Postnatal Alveolarization by Promoting Pulmonary Angiogenesis via Vascular Endothelial Growth Factor Receptor-2 Regulation
Authors: Cristina M Alvira, Tero P Alastalo, Chihhsin Chen, Shu-Chen Lyu, Yong-Tae Ahn, David N Cornfield
Journal: Circulation (2009)

Vascular development drives alveolarization via vascular endothelial growth factor receptor-2 (VEGFR-2) signaling. Chronic lung disease of infancy, bronchopulmonary dysplasia (BPD) results from arrested alveolar and vascular development. However, the transcription factors that control alveolarization are unknown. Recent data identified a novel, developmentally regulated, anti-inflammatory role for the transcription factor nuclear factor kappa B (NF κ B) in the neonatal lung, as opposed to its recognized, pro-inflammatory role in the mature lung. Thus, we hypothesized that NF κ B is essential for alveolarization. To test this hypothesis, neontal mice were treated with the NF κ B inhibitor, BAY 11–7082 (BAY), or vehicle (PBS). At 8h, lung was procured for gene and protein expression. At 24h, lungs were fixed at 25 cm H2O pressure for morphometric analysis, determination of apoptosis (TUNEL), and immunohistochemistry (IHC) to detect proliferating cell nuclear antigen (PCNA) and capillary density (CD31). Chromatin immunoprecipitation (ChIP) was performed on lung tissue to evaluate if the NF κ B subunit, p65, binds the VEGFR2 promoter. Pulmonary endothelial cells (EC) were isolated using CD31 coated beads to determine VEGFR2 expression and VEGF-mediated survival and proliferation. At 8h, NF κ B blockade (BAY) decreased VEGFR2 mRNA and protein in the lung (p&lt;0.01, versus PBS). At 24h, lungs of BAY treated mice had increased alveolar area (p&lt;0.05) and decreased radial alveolar counts (p&lt;0.01), in association with decreased capillary density (p&lt;0.01), reduced proliferation (p&lt;0.001), and increased apoptosis (p&lt;0.05). ChIP demonstrated that, in control lungs, p65 binds the VEGFR2 promoter. Furthermore, NF κ B blockade with BAY caused a dose-dependent reduction of VEGFR2 mRNA and protein in pulmonary EC, and impaired VEGF mediated EC survival and proliferation. In summary, NF κ B blockade disrupts postnatal alveolarization by decreasing VEGFR2, demonstrating that NF κ B promotes alveologenesis through VEGFR2 mediated pulmonary EC survival and proliferation. We speculate that during lung development: NF κ B promotes lung angiogenesis; and impaired NF κ B activity may play a causal role in the arrest of alveolar formation characteristic of BPD. This research has received full or partial funding support from the American Heart Association, National Center.
Notifiable Genetic Variants on Commercially Available SNP Arrays: Implications for Research Participants in Genome-wide Association Studies For Cardiovascular Disease
Authors: Andrew D Johnson
Journal: Circulation (2009)

Abstract #1806 Andrew D Johnson, NHLBI’s The Framingham Heart Study, Framingham, MA; Anupama Bhimavarapu, Harvard Medical Sch, Cambridge, MA; Emelia J Benjamin, Boston Univ, Boston, MA; Caroline Fox, Daniel Levy, NHLBI’s The Framingham Heart Study, Framingham, MA; Gail P Jarvik, Washington Univ, Seattle, WA; Christopher J O’Donnell, NHLBI’s The Framingham Heart Study, Framingham, MA Andrew D Johnson, 2009 Finalist and Presenting Author
Abstract 5148: Coexistence of Functional Angiotensin II Type 2 Receptors Mediating Both Vasoconstriction and Vasodilation in the Human Forearm Circulation
Authors: Francesca Schinzari, Manfredi Tesauro, Valentina Rovella, Nadia Mores, Carmine Cardillo
Journal: Circulation (2009)

Angiotensin (Ang) II type 2 (AT 2 ) receptors have been shown to mediate vasodilation in animal models, but data to support this concept in humans have failed to clearly define AT 2 receptor-dependent effects. In this study, therefore, we investigated the hemodynamic response to modulation of AT 2 receptors under different conditions in healthy humans (n=7) by use of the forearm perfusion technique. Intra-arterial infusion of graded doses of Ang II (12.5, 25 and 50 pmol/min) led to concentration-dependent vasoconstriction (−51±4% [mean±SEM] was the maximum decrease in forearm blood flow (FBF) from baseline; P&lt;0.001). The Ang II type 1 receptor antagonist telmisartan (30 μ g/min) induced a mild increase in unstimulated FBF (15±5%; P=0.10) and reversed the vasoconstrictor effect of Ang II into vasodilation (15±4%; P=0.02). The AT 2 receptor antagonist PD 123,319 (10 μ g/min) also resulted in a mild vasodilation (16±3%; P=0.08) and blunted the vasoconstrictor effect of Ang II (−8±3%; P=0.57). Most importantly, combined infusion of telmisartan and PD 123,319 was associated with a greater vasodilator effect (28±5%; P=0.02) than separate blockade of each Ang II receptor subtype; this response was unrelated to endothelial, nitric oxide (NO)-dependent mechanisms, because it was unaffected (27±5%; P=0.03) by the “NO clamp” (NO synthase inhibitor L-NMMA (4 μ mol/min) coinfused with the NO donor sodium nitroprusside (0.2 to 0.4 μ g/min) in order to simulate normal basal NO activity during complete inhibition of NO synthesis). By contrast, AT 2 receptor challenging with the ligand CGP 42112A (2 and 4 μ g/min) resulted in a vasodilator response (37±5% at the highest dose; P=0.02) that was abolished by the NO clamp (3±1%; P=0.94). In conclusion, AT 2 receptors contributing to Ang II-mediated vasoconstriction, likely located on vascular smooth muscle, coexist in the human forearm circulation with functional endothelial AT 2 receptors, mediating NO-dependent vasodilation. These results suggest that imbalance between these opposing effects in conditions with endothelial dysfunction contribute to Ang II-mediated vascular damage. Our current findings might also have implications for strategies targeting Ang II for treatment of hypertension.
Abstract 4756: Evaluation of the Peri-strut Low Intensity Area Following Sirolimus- and Paclitaxel-Eluting Stents Implantation: Insights From an Optical Coherence Tomography Study in Humans
Authors: Hiromasa Otake, Fumiaki Ikeno, Toshiro Shinke, Tomohiko Teramoto, Takahiro Sawada, Naoki Miyoshi, Junya Ako, Yasuhiro Honda, Paul G Yock, Peter J Fitzgerald, Ken-ichi Hirata
Journal: Circulation (2009)

Background: In previous pathological studies, paclitaxel-eluting stents (PES) showed greater fibrin deposition around stent struts, while sirolimus-eluting stent (SES) showed predominance of inflammatory cells with less fibrin deposition than PES. However, there are limited in-vivo data clarifying those qualitative differences in the process of vascular healing after 1st-generation drug-eluting stents (DES) implantation. A recent animal study has shown that peri-strut low intensity area (PLIA) seen in optical coherence tomography (OCT) imaging might represent the process of hyaluronic acid and proteoglycan replacing fibrin. Methods: A total of 60 patients who underwent 6-month follow-up OCT after SES (n=34) and PES (n=26) implantation were enrolled. PLIA was defined as a region around stent struts with a homogenous lower intensity appearance than surrounding tissue on OCT images without significant signal attenuation (Figure ). To evaluate longitudinal extent of PLIA, %PLIA was calculated for each lesion as follows: stent length with PLIA/entire stent length × 100. Results: PLIA was identified by OCT in 19 lesions in SES and 22 lesions in PES. PES showed a higher incidence of PLIA (85% vs. 56%; p=0.03, respectively) with a greater %PLIA than SES (43.0±25.6% vs. 27.8±23.1%; p=0.05, respectively). There was a positive correlation between average neointimal thickness and %PLIA in SES, while only a weak correlation was observed in PES (Figure ). Conclusions: PES showed a higher incidence of PLIA with a greater longitudinal extent of PLIA than SES. The presence and extent of PLIA appeared to be associated with neointimal proliferation after 1st-generation DES implantation.
Abstract 4849: The Dual Rho-GEF Kalirin Promotes Vascular Smooth Muscle Cell Migration and Proliferation
Authors: Lisheng Zhang, Krishn Sharma, Jiao-Hui Wu, Liisa S Smith, Leigh Brian, Sabrina T Exum, Betty A Eipper, Richard E Mains, Neil J Freedman
Journal: Circulation (2009)

Vascular smooth muscle cell (SMC) migration and proliferation are regulated by signaling through the Rho family GTPases, RhoA and Rac, which are activated by GTP exchange factors (GEFs). One such Rho-GEF was recently associated with human atherosclerosis by genetic epidemiology: kalirin, a 340 kDa protein containing both Rac- and RhoA-GEF domains. We tested the hypothesis that SMC kalirin promotes Rac or RhoA signaling, and thereby atherogenic SMC activity. By immunoblotting (IB) and quantitative immunofluorescence microscopy, we found that kalirin is expressed abundantly in SMCs, and is up-regulated 1.6±0.2-fold (p&lt;0.03) in the media of atherosclerotic, as compared with normal arteries. To test kalirin’s role in regulating SMC signaling, we compared 3 independent lines of SMCs from congenic WT and kalirin −/+ mice (with 45±5% of WT kalirin levels), as well as SMCs transfected with non-targeting or kalirin-targeting siRNA (43±9% protein knockdown). We assessed Rac and RhoA activation by G-LISA (Cytoskeleton, Inc.), and by IB for (respectively) phospho-Thr 423 -p21-activated kinase (activated Rac effector), and phospho-Ser 695 -MYPT1 of myosin light chain phosphatase (targeted only by RhoA-activated kinase). In response to FBS or PDGF, SMCs with kalirin deficiency ((−/+) or RNAi-mediated) showed reduction in the activation of Rac (by 50±10%, p&lt;0.05), but not RhoA. Moreover, SMC migration toward FBS or PDGF (8–15-fold/basal, Transwell chambers) was reduced by 30 –50% in kalirin-deficient SMCs (p&lt;0.05). FBS-induced proliferation (assessed by SMC counting) was also reduced in kalirin −/+ SMCs, by 20±5% (p&lt;0.05), even though ERK activation was not altered. To test kalirin action on SMCs in vivo, we denuded the common carotid artery endothelium with a 0.36-mm wire, a procedure we have shown (by bone marrow transplant) produces neointimal hyperplasia comprising SMCs derived only from the arterial media. Neointimal area 4 wk after wire injury was 60±10% less (p&lt;0.05) in kalirin −/+ (0.012±0.003 mm 2 ) than in WT mice (0.03±0.01 mm 2 ) matched for gender, age, and weight, even though medial area was equivalent. We conclude that kalirin is an important Rac-GEF in SMCs, and promotes SMC migration and proliferation in a manner that may prove pro-atherogenic.
Abstract 4877: Circadian Variation of Blood Pressure is Correlated to Vascular Endothelial Function in Nondiabetic Essential Hypertensives
Authors: Chin-Chou Huang, Hsin-Bang Leu, Tao-Cheng Wu, Shing-Jong Lin, Jaw-Wen Chen
Journal: Circulation (2009)

Background: Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension has been described. We assessed the hypothesis that there was relationship between the circadian rhythm of blood pressure and endothelial function in patients with essential hypertension. Methods: Non-diabetic patients with either treated or untreated essential hypertension were evaluated if their office systolic blood pressure (SBP) ≥140 mmHg or diastolic blood pressure (DBP) ≥90 mmHg. Serial studies including 24-hour ambulatory blood pressure monitoring, serum biomarkers, and brachial artery ultrasound were arranged. Results: Thirty-nine patients were enrolled into the study. They were subclassified by their nocturnal DBP fall (25 dippers, with nocturnal DBP fall ≥10%; and 14 non-dippers, with nocturnal DBP fall &lt;10%). The baseline characteristics and serum biomarkers including adiponectin, asymmetric dimethylargine, oxidized low-density lipoprotein, monocyte chemoattractant protein-1, high-sensitivity C-reactive protein, insulin, and nitrate and nitrite were similar between the 2 groups. The flow-mediated dilation (FMD) of brachial artery was greater in the dippers than in the non-dippers (6.1±3.1% vs. 4.1±2.6%, p =0.04) while the nitroglycerin-mediated dilation of brachial artery was similar between the two groups (14.3±5.5% vs. 13.7±6.0%, p =0.746). In all patients, sleep DBP (r=−0.379, p =0.017), nocturnal change of SBP (r=0.344, p =0.032) and DBP (r=0.420, p =0.008), and the use of calcium channel blockers (r=−0.394, p =0.013) were correlated to FMD. In multivariate analysis, only nocturnal change of DBP was the independent predictor for FMD ( β =0.175, p =0.008). Conclusions: In non-diabetic hypertensive patients, the dippers had better endothelial function than the non-dippers. Nocturnal change of DBP was the major predictor for endothelial function.
Abstract 5117: Sustained Release of Granulocyte Colony-Stimulating Factor Using Biodegradable Gelatin Hydrogel Microspheres Persistently Improves Blood Flow of Ischemic Limbs in Mice
Authors: Itta Kawamura, Genzou Takemura, Hiromitsu Kanamori, Longhu Li, Hideshi Okada, Masayasu Esaki, Hiroyuki Kobayashi, Akiko Tsujimoto, Kazuko Goto, Rumi Maruyama, Toshiaki Takeyama, Tomonori Kawaguchi, Takatomo Watanabe, Arihiro Hattori, Hiroaki Ushikoshi, Takuma Aoyama, Masanori Kawasaki, Kazuhiko Nishigaki, Hisayoshi Fujiwara, Yasuhiko Tabata, Shinya Minatoguchi
Journal: Circulation (2009)

Granulocyte colony-stimulating factor (G-CSF) is a potent angiogenetic factor, but its use is limited because of the unfavorable systemic effects. We hypothesized that G-CSF immersed gelatin hydrogel microspheres (GHM) injected into the ischemic limb might continuously release a small amount of G-CSF to locally stimulate angiogenesis without adverse effects. We ligated the right femoral artery of BALB/c mice and randomly assigned mice into 5 groups: the saline group with a single intramuscular injection of saline into the ischemic limb; the G-CSF sc group with a subcutaneus injection of G-CSF (100 μ g/kg) for 5 days; the G-CSF im group with an intramuscular injection of G-CSF (20 μ g/kg) into the ischemic limb for 5 days: the GHM group with a single intramuscular injection of GHM alone into the ischemic limb; and the G-CSF-GHM group with a single intramuscular injection of G-CSF (100 μ g/kg) immersed GHM into the ischemic limb. The blood flow ratio of the ischemic/non-ischemic limb assessed by a laser Doppler perfusion imager became significantly improved 6 weeks later in the G-CSF-GHM group compared with the other groups and lasted until 8 weeks (saline; 0.63±0.10, G-CSF sc; 0.70±0.14, G-CSF im; 0.61±0.15, GHM; 0.59±0.12, G-CSF-GHM; 0.88±0.20). Both in the G-CSF sc and im groups, the blood flow ratio was significantly improved at the early time (1 and 2 weeks later in the G-CSF sc group, 3days later in the G-CSF im group), but was only transient. Not only capillaries but also arterioles were significantly increased in the G-CSF-GHM group where granulocyte and endothelial progenitor cell counts were not elevated but the Akt/endothelial nitric oxide synthase pathway in the ischemic limb was significantly activated. The present drug delivery system is suggested to have potential as a novel noninvasive therapy in patients with peripheral artery disease because of not only its efficacy but also less invasiveness and less unfavorable systemic effect.
Abstract 4894: Risk Factors for Hypertension Incidence in Type 1 Diabetes: The Pittsburgh Epidemiology of Diabetes Complications Study
Authors: Tina Costacou, Trevor J Orchard
Journal: Circulation (2009)

Recent analyses of the DCCT/EDIC demonstrated that hyperglycemia and intensive insulin therapy are associated with incident hypertension. We assessed this hypothesis in a population based cohort study of individuals with type 1 diabetes mellitus. Participants of the Pittsburgh Epidemiology of Diabetes Complications Study, a prospective cohort of childhood onset type 1 diabetes (at baseline, mean age was 28 years and mean diabetes duration 19 years), free of hypertension at baseline, were selected for study (n = 510). Hypertension incidence was defined as systolic blood pressure &gt;140 mmHg, or diastolic blood pressure &gt;90 mmHg, or use of medication for the treatment of high blood pressure in two consecutive study visits. Intensive insulin therapy (IIT) was defined as ≥3 injections (or pump) and ≥4 glucose tests daily. Predictors of hypertension incidence were examined using multivariable Cox proportional hazard models with backward elimination. During 18 years of follow-up, 200 (39.2%) incident cases of hypertension occurred. At study entry, incident cases were more likely to be older, have longer diabetes duration, higher levels of body mass index, HbA1, blood pressure, pulse, non-HDL cholesterol, albumin excretion rate and inflammatory markers and lower HDL cholesterol and were more likely to have had a diagnosis of confirmed distal symmetric polyneuropathy, microalbuminuria, and overt nephropathy compared to non-cases. Cases were also less likely to practice IIT. In multivariable models, significant independent predictors of hypertension incidence consisted of HbA1 (HR = 1.16, 95% CI = 1.05–1.30), IIT (HR = 0.46, 95% CI = 0.19 –1.13, p = 0.09), insulin dose per weight (HR = 0.56, 95% CI = 0.30 –1.04), systolic blood pressure (HR = 1.05, 95% CI = 1.03–1.06), pulse (HR = 1.02, 95% CI = 1.00 –1.03), albumin excretion rate (HR = 1.28 –1.17–1.39) and presence of proliferative retinopathy (HR = 1.48, 95% CI = 1.03–2.13) and coronary artery disease (HR = 1.83, 95% CI = 0.95–3.55). In conclusion, hyperglycemia is a risk factor for the development of hypertension among individuals with long-standing type 1 diabetes. Moreover, as reported in DCCT, IIT is inversely related with hypertension incidence.
Stromal Cell–Derived Factor-1 <i>α</i> Activation of Tissue Engineered Endothelial Progenitor Stem Cell Matrix Enhances Ventricular Function After Myocardial Infarction by Inducing Neovasculogenesis
Authors: John R Frederick
Journal: Circulation (2009)

Abstract #4221 John R Frederick, J. Raymond Fitzpatrick III, Ryan C McCormick, David A Harris, Ah-Young Kim, Jeffrey R Muenzer, Ashwin Murthy, Univ of Pennsylvania Sch of Med, Philadelphia, PA; Philip F Hsiao, Alisha D Prystowsky, Univ of Pennsylvania, Philadelphia, PA; Maximilian J Smith, Jeffrey Cohen, Pavan Atluri, Y. Joseph Woo, Univ of Pennsylvania Sch of Med, Philadelphia, PA John R Frederick, 2009 Finalist and Presenting Author