Corey Goldman - Academia.edu (original) (raw)

Papers by Corey Goldman

Research paper thumbnail of Epidermal growth factor stimulates vascular endothelial growth factor production by human malignant glioma cells: a model of glioblastoma multiforme pathophysiology

Molecular Biology of the Cell, 1993

Hypervascularity, focal necrosis, persistent cerebral edema, and rapid cellular proliferation are... more Hypervascularity, focal necrosis, persistent cerebral edema, and rapid cellular proliferation are key histopathologic features of glioblastoma multiforme (GBM), the most common and malignant of human brain tumors. By immunoperoxidase and immunofluorescence, we definitively have demonstrated the presence of vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFr) in five out of five human glioma cell lines (U-251MG, U-105MG, D-65MG, D-54MG, and CH-235MG) and in eight human GBM tumor surgical specimens. In vitro experiments with glioma cell lines revealed a consistent and reliable relation between EGFr activation and VEGF production; namely, EGF (1-20 ng/ml) stimulation of glioma cells resulted in a 25-125% increase in secretion of bioactive VEGF. Conditioned media (CM) prepared from EGF-stimulated glioma cell lines produced significant increases in cytosolic free intracellular concentrations of Ca21 ([Ca2+]i) in human umbilical vein endothelial cells (HUVECs). Neither EGF alone or CM from glioma cultures prepared in the absence of EGF induced [Ca21]i increases in HUVECs. Preincubation of glioma CM with A4.6.1, a monoclonal antibody to VEGF, completely abolished VEGFmediated [Ca21]i transients in HUVECs. Likewise, induction by glioma-derived CM of von Willebrand factor release from HUVECs was completely blocked by A4.6.1 pretreatment. These observations provide a key link in understanding the basic cellular pathophysiology of GBM tumor angiogenesis, increased vascular permeability, and cellular proliferation. Specifically, EGF activation of EGFr expressed on glioma cells leads to enhanced secretion of VEGF by glioma cells. VEGF released by glioma cells in situ most likely accounts for pathognomonic histopathologic and clinical features of GBM tumors in patients, including striking tumor angiogenesis, increased cerebral edema and hypercoagulability manifesting as focal tumor necrosis, deep vein thrombosis, or pulmonary embolism.

Research paper thumbnail of Abstract 3308: New Doppler Ultrasound Criteria for Renal Artery In-Stent Restenosis

Circulation

Background: Renal artery Doppler ultrasound (DUS) has been well established as an effective non-i... more Background: Renal artery Doppler ultrasound (DUS) has been well established as an effective non-invasive screening tool for renal artery stenosis in native renal arteries. Stent placement alters the elastic properties of arteries and would be expected to decrease arterial compliance resulting in higher DUS velocities than non-stented arteries. To date, no criteria have been established for detecting in-stent restenosis (ISR) with DUS. Purpose: To establish the optimal DUS parameters to detect hemodynamically significant renal artery in-stent restenosis. Methods: We included consecutive patients (N=68) with clinically suspected renal artery ISR. Each patient underwent DUS and quantitative renal angiography that were blindly interpreted. Pearson’s correlation coefficients of 0.80 to 0.87 (P<0.0001) suggested strong agreement among observers. Significant ISR was defined as ≤ 70% reduction of in-stent luminal diameter when compared to the nearest normal reference segment. Angiographi...

Research paper thumbnail of Abstract 1209: Bone Morphogenic Protein-4 is Elevated in Chronic Kidney Disease Patients with Coronary Artery Disease

Circulation, Oct 31, 2006

Cross-sectional studies have demonstrated that the Framingham Risk Equation does not adequately p... more Cross-sectional studies have demonstrated that the Framingham Risk Equation does not adequately predict the magnitude of the increased risk of cardiovascular disease seen in chronic kidney disease (CKD) patients, suggesting additional risk factors may be present in CKD patients. Recent studies suggest that the increased vascular calcification seen in CKD patients compared with the general population may play a role in the increased risk of cardiovascular events. One mechanism proposed for the induction of vascular calcification is the up-regulation of the bone morphogenic proteins (BMP) at the site of vascular calcification. We measured the levels of BMP-4 in the plasma of healthy volunteers (n=11) and patients with coronary artery disease (CAD) without CKD (n=10), CKD without CAD (n=6), and CKD with CAD (n=7). CKD was defined as Stage 3, 4, or 5 kidney disease using the National Kidney Foundation’s KDOQI classification. CAD was defined as a greater than 50% narrowing of a coronary artery determined angio...

Research paper thumbnail of Gene therapy for inhibition of angiogenesis

Research paper thumbnail of Detection of chronic kidney disease patients or coronary artery disease using bone morphogenic protein-4

Research paper thumbnail of Compounds for the Inhibition of Angiogenesis by Gene Therapy

Research paper thumbnail of Abstract 3013: Clinical Utility of Doppler Ultrasound Imaging for Screening of In-Stent Restenosis of Renal Arteries

Circulation, Oct 31, 2006

Research paper thumbnail of ACCF/AHA 2007 Clinical Competence Statement on Vascular Imaging With Computed Tomography and Magnetic Resonance A Report of the American College of Cardiology Foundation/American Heart Association/American College of Physicians Task Force on Clinical Competence and Training

Research paper thumbnail of Enhancement of Epigastric Skin Flap Survival by Adenovirus-Mediated VEGF Gene Therapy

Plastic and Reconstructive Surgery, 2002

Research paper thumbnail of In vitro and in vivo gene delivery mediated by a synthetic polycationic amino polymer

Nature Biotechnology, 1997

Research paper thumbnail of Practice Guideline for Adult Antibiotic Prophylaxis during Vascular and Interventional Radiology Procedures

Journal of Vascular and Interventional Radiology, 2010

Guidelines Task Force (4,5). A summary of these definitions are provided in Appendix B.

Research paper thumbnail of Vascular endothelial growth factor in human glioma cell lines: induced secretion by EGF, PDGF-BB, and bFGF

Journal of Neurosurgery, 1995

✓ Vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) is an endothelial ce... more ✓ Vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) is an endothelial cell—specific mitogen that is structurally related to platelet-derived growth factor (PDGF). Vascular endothelial growth factor/vascular permeability factor induces angiogenesis in vivo and may play a critical role in tumor angiogenesis. Using immunohistochemical analysis, the authors demonstrated the presence of VEGF/VPF protein in surgical specimens of glioblastoma multiforme and cultured glioma cells. By means of an enzyme-linked immunosorbent assay (ELISA) of cell supernatants, the authors showed that VEGF/VPF is variably secreted by all nine cultured human malignant glioma cell lines (CH-235MG, D-37MG, D-54MG, D-65MG, U-87MG, U-105MG, U-138MG, U-251MG, U-373MG) and by a single meningioma cell line (CH-157MN). An immunocytochemical survey of these cell lines revealed a cytoplasmic and cell-surface distribution of VEGF/VPF. In the U-105MG glioma cell line, VEGF/VPF secretion was induced...

Research paper thumbnail of Enhancement of Muscle Flap Hemodynamics by Angiopoietin-1

Annals of Plastic Surgery, 2002

Angiopoietin-1 (Ang-1) constitutes a novel family of endothelial cell-specific angiogenic factors... more Angiopoietin-1 (Ang-1) constitutes a novel family of endothelial cell-specific angiogenic factors. Ang-1 functions mainly in remodeling, maturation, and stabilization of blood vessels. Its direct role in the process of angiogenesis remains unknown. The authors designed an experimental study to investigate the angiogenic potential of Ang-1 and to determine its hemodynamic effects on the cremaster muscle flap model in the rat. Adenovirus-mediated gene therapy was used for delivery of Ang-1. The study sample included 45 male Sprague-Dawley rats weighing 200 to 250 g. After the cremaster muscle tube flaps were prepared, rats were randomized into three different groups of 15 animals. In group I (the control), the flaps received phosphate-buffered saline (PBS). In group II, flaps were treated with adenovirus vector encoding Ang-1 (Ad-Ang-1). In group III, flaps received a control gene encoding green fluorescein protein (Ad-GFP). All treatments were administered via intra-arterial injections of either viral particles (10 8 placque-forming units) or PBS. The external iliac artery was used for this purpose. The cremaster tube flap was then preserved in a subcutaneous pocket in the lower limb. The tube flap was withdrawn from the limb on days 3, 7, and 14 after intra-arterial injection to evaluate microcirculatory measurements such as red blood cell velocity, vessel diameter, capillary density, and microvascular permeability by intravital microscopy. Evaluations were performed by an investigator who was blinded to treatment groups. In a series of control experiments performed with Ad-GFP, adenoviral gene expression was evidenced by the observation of shiny GFP deposits along the vessel walls under fluorescence microscopy throughout the whole cremaster flap 2 days after transfection. At day 3 there was no evidence of any differences in capillary density and permeability index (PI). At day 7, the functional capillary density was significantly higher in the Ad-Ang-1-treated group compared with the control and the Ad-GFP groups (10/hpf ؎ 2 vs. 7/hpf ؎ 0.5, p ‫؍‬ 0.006; 5/hpf ؎ 1.6, p ‫؍‬ 0.0001). The PI in the Ad-Ang-1-treated group was significantly lower compared with the Ad-GFP-treated group (1.1/hpf ؎ 0.1% vs. 1.4/hpf ؎ 0.1%, p ‫؍‬ 0.0005). At 14 days, the number of the flowing capillaries was significantly higher in the Ad-Ang-1treated group compared with the control and the Ad-GFP-treated groups (13/hpf ؎ 1.7 vs. 9/hpf ؎ 2 and 6/hpf ؎ 1.3, p ‫؍‬ 0.0001). The microvascular PI was significantly lower in the Ad-Ang-1-treated group compared with the Ad-GFP-treated group (1.3/hpf ؎ 0.2% vs. 1.8/hpf ؎ 0.5%, p ‫؍‬ 0.004). Histologically, the cremaster flaps revealed focal and mild inflammation regardless of the treatment and time point of evaluation. There was evidence of vasculitis in muscles pretreated with Ad-GFP and Ad-Ang-1. In summary, in the Ad-Ang-1-treated cremaster flaps, functional capillary density increased from 46% at day 7 to 98% at day 14 when compared with the control group (p < 0.0001). In conclusion, in this experimental muscle flap model, Ad-Ang-1 treatment proved to be a successful method of angiogenic therapy, providing a long-lasting angiogenic effect over a period of 14 days. The increased capillary perfusion accompanied by the formation of more stable and mature vessels resistant to fluorescein isothiocyanate-conjugated albumin leakage may serve as in vivo evidence that Ang-1 therapy improves skeletal muscle flap hemodynamics. These exciting findings raise the possibility that Ang-1 may have implications for therapeutic angiogenesis. To the authors' knowledge, their study demonstrates for the first time the feasibility of intravascular gene therapy using a virus vector in an attempt to enhance muscle flap hemodynamics.

Research paper thumbnail of The regulation of vascular endothelial growth factors (VEGF-A, -C, and -D) expression in the retinal pigment epithelium

American Journal of Ophthalmology, 2007

The vascular endothelial growth factor (VEGF) family plays an essential role in vascular developm... more The vascular endothelial growth factor (VEGF) family plays an essential role in vascular development, angiogenesis and lymphangiogenesis. VEGF-A is a key regulator of endothelial cell functions and VEGF-C and VEGF-D are known to stimulate both angiogenesis and lymphangiogenesis.Inasurgicallyremovedsubretinalvascularmembraneofanage-relatedmaculardegeneration(AMD)patient,bothVEGF-CandVEGF-Dwere confirmed,inadditiontoVEGF-A,tobemarkedlypositiveintheretinalpigmentepithelium(RPE).Thereisnolymphvesselinoculartissue,soitis possible that VEGF-C and VEGF-D expression in the RPE play some role in ocular angiogenesis, as well as VEGF-A. Next, we assessed the transition of VEGF-A, -C, and -D expression on several conditions, in human RPE. Hypoxia proverbially induced VEGF-A mRNA expression, meanwhile VEGF-C and VEGF-D mRNA expression was down-regulated. The Ca 2þ deprivation from culture medium strongly up-regulated VEGF-A and VEGF-D mRNA expression. Culture on plastic flasks precoated with poly-2-hydroxyethyl methacrylate up-regulated VEGF-D expression. Meanwhile, no significant change of VEGF-C mRNA expression was found in the blockade of cellecell and/or cellematrix adhesion. These findings suggest the possibility that VEGF-C and VEGF-D expression in RPE modify the ocular angiogenesis as angiogenic stimulators. 2006 Elsevier Ltd. All rights reserved.

Research paper thumbnail of Loss of Vascular Endothelial Growth Factor in Human Alopecia Hair Follicles

Journal of Investigative Dermatology, 1995

hair, whereas subsequent generations of hair have difficulty forming because the follicles are di... more hair, whereas subsequent generations of hair have difficulty forming because the follicles are distorted and the distal end can become separated from the rest of the follicle [5]. Skin samples were obtained from the dorsal region of hairless mutant mice and unaffected littermates; the samples were fixed and paraffin embedded. Tissue sections (5 /Lm) were deparaffinized, then probed with a polyclonal antibody against FGF-2 (a kind gifr of Dr. M.

Research paper thumbnail of Stromal cell-derived factor-1 mediates stem cell homing and tissue regeneration

Discovery medicine, 2003

Extract: The search for alternative treatments for congestive heart failure remains an ongoing ve... more Extract: The search for alternative treatments for congestive heart failure remains an ongoing venture. Exciting research over the last 2 years has changed the long held dogma that the heart cannot regenerate itself. The work of many groups can be summarized by the following concept: increasing the number of CD117+ (c-kit+) stem cells in cardiac tissue or in the coronary circulation within 2 days of a myocardial infarction results in regeneration of myocardial tissue and improved cardiac function. Animal studies by Orlic, Anversa and colleagues have demonstrated that either the direct injection of bone marrow-derived CD117+ stem cells in the infarct border zone at the time of myocardial infarction, or mobilization of these stem cells prior to myocardial infarction results in regeneration of cardiac myocytes and improved left ventricular (LV) function. In a critical experiment, Itescu and colleagues extended the window of therapeutic opportunity by demonstrating that the intravenous ...

Research paper thumbnail of dilated ischemic cardiomyopathy factor results in improved left ventricular function and neovascularization in Cellular, but not direct, adenoviral delivery of vascular endothelial growth

We sought to compare the effects on angiogenesis and left ventricular (LV) function of adenoviral... more We sought to compare the effects on angiogenesis and left ventricular (LV) function of adenoviral vascular endothelial growth factor-165 (AdVEGF-165) gene delivery by direct injection of AdVEGF-165 to the transplantation of skeletal myoblasts (SKMB) transfected with AdVEGF-165 in a rat model of ischemic cardiomyopathy. BACKGROUND Angiogenesis offers the potential for treating ischemic cardiomyopathy. However, the optimal method of delivering angiogenic factors for neovascularization remains undetermined. With the increased clinical interest in cell therapy for the treatment of LV dysfunction, SKMB transplantation may serve as a means of gene transfer. METHODS Two months after left anterior descending coronary artery ligation, rats received either injection of an adenoviral construct encoding VEGF-165, or 1 million SKMB transfected with AdLuciferase (AdLuc) or AdVEGF-165. Cardiac function was assessed echocardiographically, and neovascularization was assessed histologically four weeks after therapy. RESULTS Neovascularization was significantly increased by both AdVEGF delivery strategies (100 Ϯ 7% and 185 Ϯ 33% increase in vascular density compared with SKMB alone, respectively). However, cell-based delivery, but not direct injection of AdVEGF-165, resulted in increased cardiac function (73.5 Ϯ 12.6% and 1.5 Ϯ 8.8% increase in shortening fraction compared with saline control; AdLuc-transfected SKMB: 29.4 Ϯ 15.0%). The improved function was not due to increased engraftment of VEGF expressing SKMB. Rather, improved function correlated with less apoptosis in the border zone in those animals that received AdVEGF-165 expressing SKMB. CONCLUSION Our data demonstrate that cell-based delivery of VEGF leads to an improved treatment effect over direct adenoviral injection, and suggest that already developed adenoviral vectors that encode secreted factors could potentially offer greater efficacy in combination with SKMB transplantation.

Research paper thumbnail of CT angiography of the lower extremity circulation with protocols

Practical Approach with Clinical Protocols, 2007

Invasive digital subtraction angiography is the traditional method by which disease of the lower ... more Invasive digital subtraction angiography is the traditional method by which disease of the lower extremities has been assessed, but it is an expensive and time-consuming procedure with a complication rate of approximately 2–3%. To avoid unnecessary invasive diagnostic ...

Research paper thumbnail of What's Calcium's role in heart and kidney disease?

Research paper thumbnail of Targeted gene delivery to Kaposi's sarcoma cells via the fibroblast growth factor receptor

Cancer research, Jan 15, 1997

Kaposi's sarcoma (KS) is a major AIDS-related malignancy associated with significant morbidit... more Kaposi's sarcoma (KS) is a major AIDS-related malignancy associated with significant morbidity and mortality. Current chemotherapeutic regimens are associated with a dismal prognosis. In an effort to develop a new approach to KS treatment, we devised a gene therapy-based adenovirus retargeting schema that redirects the adenovirus to fibroblast growth factor receptors endogenously present on the cell surface of KS cells. By using a bifunctional conjugate consisting of a blocking antiadenoviral knob Fab linked to basic fibroblast growth factor, FGF2, the gene transduction of KS cells was enhanced 7.7-44 fold; recombinant adenoviruses encoding either the firefly luciferase reporter gene, or the herpes simplex thymidine kinase gene, demonstrated quantitative enhancement of expression in the KS cell lines. In this regard, two KS cell lines that were previously refractory to native adenovirus transduction could be successfully transduced by the addition of the conjugate. This study th...

Research paper thumbnail of Epidermal growth factor stimulates vascular endothelial growth factor production by human malignant glioma cells: a model of glioblastoma multiforme pathophysiology

Molecular Biology of the Cell, 1993

Hypervascularity, focal necrosis, persistent cerebral edema, and rapid cellular proliferation are... more Hypervascularity, focal necrosis, persistent cerebral edema, and rapid cellular proliferation are key histopathologic features of glioblastoma multiforme (GBM), the most common and malignant of human brain tumors. By immunoperoxidase and immunofluorescence, we definitively have demonstrated the presence of vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFr) in five out of five human glioma cell lines (U-251MG, U-105MG, D-65MG, D-54MG, and CH-235MG) and in eight human GBM tumor surgical specimens. In vitro experiments with glioma cell lines revealed a consistent and reliable relation between EGFr activation and VEGF production; namely, EGF (1-20 ng/ml) stimulation of glioma cells resulted in a 25-125% increase in secretion of bioactive VEGF. Conditioned media (CM) prepared from EGF-stimulated glioma cell lines produced significant increases in cytosolic free intracellular concentrations of Ca21 ([Ca2+]i) in human umbilical vein endothelial cells (HUVECs). Neither EGF alone or CM from glioma cultures prepared in the absence of EGF induced [Ca21]i increases in HUVECs. Preincubation of glioma CM with A4.6.1, a monoclonal antibody to VEGF, completely abolished VEGFmediated [Ca21]i transients in HUVECs. Likewise, induction by glioma-derived CM of von Willebrand factor release from HUVECs was completely blocked by A4.6.1 pretreatment. These observations provide a key link in understanding the basic cellular pathophysiology of GBM tumor angiogenesis, increased vascular permeability, and cellular proliferation. Specifically, EGF activation of EGFr expressed on glioma cells leads to enhanced secretion of VEGF by glioma cells. VEGF released by glioma cells in situ most likely accounts for pathognomonic histopathologic and clinical features of GBM tumors in patients, including striking tumor angiogenesis, increased cerebral edema and hypercoagulability manifesting as focal tumor necrosis, deep vein thrombosis, or pulmonary embolism.

Research paper thumbnail of Abstract 3308: New Doppler Ultrasound Criteria for Renal Artery In-Stent Restenosis

Circulation

Background: Renal artery Doppler ultrasound (DUS) has been well established as an effective non-i... more Background: Renal artery Doppler ultrasound (DUS) has been well established as an effective non-invasive screening tool for renal artery stenosis in native renal arteries. Stent placement alters the elastic properties of arteries and would be expected to decrease arterial compliance resulting in higher DUS velocities than non-stented arteries. To date, no criteria have been established for detecting in-stent restenosis (ISR) with DUS. Purpose: To establish the optimal DUS parameters to detect hemodynamically significant renal artery in-stent restenosis. Methods: We included consecutive patients (N=68) with clinically suspected renal artery ISR. Each patient underwent DUS and quantitative renal angiography that were blindly interpreted. Pearson’s correlation coefficients of 0.80 to 0.87 (P<0.0001) suggested strong agreement among observers. Significant ISR was defined as ≤ 70% reduction of in-stent luminal diameter when compared to the nearest normal reference segment. Angiographi...

Research paper thumbnail of Abstract 1209: Bone Morphogenic Protein-4 is Elevated in Chronic Kidney Disease Patients with Coronary Artery Disease

Circulation, Oct 31, 2006

Cross-sectional studies have demonstrated that the Framingham Risk Equation does not adequately p... more Cross-sectional studies have demonstrated that the Framingham Risk Equation does not adequately predict the magnitude of the increased risk of cardiovascular disease seen in chronic kidney disease (CKD) patients, suggesting additional risk factors may be present in CKD patients. Recent studies suggest that the increased vascular calcification seen in CKD patients compared with the general population may play a role in the increased risk of cardiovascular events. One mechanism proposed for the induction of vascular calcification is the up-regulation of the bone morphogenic proteins (BMP) at the site of vascular calcification. We measured the levels of BMP-4 in the plasma of healthy volunteers (n=11) and patients with coronary artery disease (CAD) without CKD (n=10), CKD without CAD (n=6), and CKD with CAD (n=7). CKD was defined as Stage 3, 4, or 5 kidney disease using the National Kidney Foundation’s KDOQI classification. CAD was defined as a greater than 50% narrowing of a coronary artery determined angio...

Research paper thumbnail of Gene therapy for inhibition of angiogenesis

Research paper thumbnail of Detection of chronic kidney disease patients or coronary artery disease using bone morphogenic protein-4

Research paper thumbnail of Compounds for the Inhibition of Angiogenesis by Gene Therapy

Research paper thumbnail of Abstract 3013: Clinical Utility of Doppler Ultrasound Imaging for Screening of In-Stent Restenosis of Renal Arteries

Circulation, Oct 31, 2006

Research paper thumbnail of ACCF/AHA 2007 Clinical Competence Statement on Vascular Imaging With Computed Tomography and Magnetic Resonance A Report of the American College of Cardiology Foundation/American Heart Association/American College of Physicians Task Force on Clinical Competence and Training

Research paper thumbnail of Enhancement of Epigastric Skin Flap Survival by Adenovirus-Mediated VEGF Gene Therapy

Plastic and Reconstructive Surgery, 2002

Research paper thumbnail of In vitro and in vivo gene delivery mediated by a synthetic polycationic amino polymer

Nature Biotechnology, 1997

Research paper thumbnail of Practice Guideline for Adult Antibiotic Prophylaxis during Vascular and Interventional Radiology Procedures

Journal of Vascular and Interventional Radiology, 2010

Guidelines Task Force (4,5). A summary of these definitions are provided in Appendix B.

Research paper thumbnail of Vascular endothelial growth factor in human glioma cell lines: induced secretion by EGF, PDGF-BB, and bFGF

Journal of Neurosurgery, 1995

✓ Vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) is an endothelial ce... more ✓ Vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) is an endothelial cell—specific mitogen that is structurally related to platelet-derived growth factor (PDGF). Vascular endothelial growth factor/vascular permeability factor induces angiogenesis in vivo and may play a critical role in tumor angiogenesis. Using immunohistochemical analysis, the authors demonstrated the presence of VEGF/VPF protein in surgical specimens of glioblastoma multiforme and cultured glioma cells. By means of an enzyme-linked immunosorbent assay (ELISA) of cell supernatants, the authors showed that VEGF/VPF is variably secreted by all nine cultured human malignant glioma cell lines (CH-235MG, D-37MG, D-54MG, D-65MG, U-87MG, U-105MG, U-138MG, U-251MG, U-373MG) and by a single meningioma cell line (CH-157MN). An immunocytochemical survey of these cell lines revealed a cytoplasmic and cell-surface distribution of VEGF/VPF. In the U-105MG glioma cell line, VEGF/VPF secretion was induced...

Research paper thumbnail of Enhancement of Muscle Flap Hemodynamics by Angiopoietin-1

Annals of Plastic Surgery, 2002

Angiopoietin-1 (Ang-1) constitutes a novel family of endothelial cell-specific angiogenic factors... more Angiopoietin-1 (Ang-1) constitutes a novel family of endothelial cell-specific angiogenic factors. Ang-1 functions mainly in remodeling, maturation, and stabilization of blood vessels. Its direct role in the process of angiogenesis remains unknown. The authors designed an experimental study to investigate the angiogenic potential of Ang-1 and to determine its hemodynamic effects on the cremaster muscle flap model in the rat. Adenovirus-mediated gene therapy was used for delivery of Ang-1. The study sample included 45 male Sprague-Dawley rats weighing 200 to 250 g. After the cremaster muscle tube flaps were prepared, rats were randomized into three different groups of 15 animals. In group I (the control), the flaps received phosphate-buffered saline (PBS). In group II, flaps were treated with adenovirus vector encoding Ang-1 (Ad-Ang-1). In group III, flaps received a control gene encoding green fluorescein protein (Ad-GFP). All treatments were administered via intra-arterial injections of either viral particles (10 8 placque-forming units) or PBS. The external iliac artery was used for this purpose. The cremaster tube flap was then preserved in a subcutaneous pocket in the lower limb. The tube flap was withdrawn from the limb on days 3, 7, and 14 after intra-arterial injection to evaluate microcirculatory measurements such as red blood cell velocity, vessel diameter, capillary density, and microvascular permeability by intravital microscopy. Evaluations were performed by an investigator who was blinded to treatment groups. In a series of control experiments performed with Ad-GFP, adenoviral gene expression was evidenced by the observation of shiny GFP deposits along the vessel walls under fluorescence microscopy throughout the whole cremaster flap 2 days after transfection. At day 3 there was no evidence of any differences in capillary density and permeability index (PI). At day 7, the functional capillary density was significantly higher in the Ad-Ang-1-treated group compared with the control and the Ad-GFP groups (10/hpf ؎ 2 vs. 7/hpf ؎ 0.5, p ‫؍‬ 0.006; 5/hpf ؎ 1.6, p ‫؍‬ 0.0001). The PI in the Ad-Ang-1-treated group was significantly lower compared with the Ad-GFP-treated group (1.1/hpf ؎ 0.1% vs. 1.4/hpf ؎ 0.1%, p ‫؍‬ 0.0005). At 14 days, the number of the flowing capillaries was significantly higher in the Ad-Ang-1treated group compared with the control and the Ad-GFP-treated groups (13/hpf ؎ 1.7 vs. 9/hpf ؎ 2 and 6/hpf ؎ 1.3, p ‫؍‬ 0.0001). The microvascular PI was significantly lower in the Ad-Ang-1-treated group compared with the Ad-GFP-treated group (1.3/hpf ؎ 0.2% vs. 1.8/hpf ؎ 0.5%, p ‫؍‬ 0.004). Histologically, the cremaster flaps revealed focal and mild inflammation regardless of the treatment and time point of evaluation. There was evidence of vasculitis in muscles pretreated with Ad-GFP and Ad-Ang-1. In summary, in the Ad-Ang-1-treated cremaster flaps, functional capillary density increased from 46% at day 7 to 98% at day 14 when compared with the control group (p < 0.0001). In conclusion, in this experimental muscle flap model, Ad-Ang-1 treatment proved to be a successful method of angiogenic therapy, providing a long-lasting angiogenic effect over a period of 14 days. The increased capillary perfusion accompanied by the formation of more stable and mature vessels resistant to fluorescein isothiocyanate-conjugated albumin leakage may serve as in vivo evidence that Ang-1 therapy improves skeletal muscle flap hemodynamics. These exciting findings raise the possibility that Ang-1 may have implications for therapeutic angiogenesis. To the authors' knowledge, their study demonstrates for the first time the feasibility of intravascular gene therapy using a virus vector in an attempt to enhance muscle flap hemodynamics.

Research paper thumbnail of The regulation of vascular endothelial growth factors (VEGF-A, -C, and -D) expression in the retinal pigment epithelium

American Journal of Ophthalmology, 2007

The vascular endothelial growth factor (VEGF) family plays an essential role in vascular developm... more The vascular endothelial growth factor (VEGF) family plays an essential role in vascular development, angiogenesis and lymphangiogenesis. VEGF-A is a key regulator of endothelial cell functions and VEGF-C and VEGF-D are known to stimulate both angiogenesis and lymphangiogenesis.Inasurgicallyremovedsubretinalvascularmembraneofanage-relatedmaculardegeneration(AMD)patient,bothVEGF-CandVEGF-Dwere confirmed,inadditiontoVEGF-A,tobemarkedlypositiveintheretinalpigmentepithelium(RPE).Thereisnolymphvesselinoculartissue,soitis possible that VEGF-C and VEGF-D expression in the RPE play some role in ocular angiogenesis, as well as VEGF-A. Next, we assessed the transition of VEGF-A, -C, and -D expression on several conditions, in human RPE. Hypoxia proverbially induced VEGF-A mRNA expression, meanwhile VEGF-C and VEGF-D mRNA expression was down-regulated. The Ca 2þ deprivation from culture medium strongly up-regulated VEGF-A and VEGF-D mRNA expression. Culture on plastic flasks precoated with poly-2-hydroxyethyl methacrylate up-regulated VEGF-D expression. Meanwhile, no significant change of VEGF-C mRNA expression was found in the blockade of cellecell and/or cellematrix adhesion. These findings suggest the possibility that VEGF-C and VEGF-D expression in RPE modify the ocular angiogenesis as angiogenic stimulators. 2006 Elsevier Ltd. All rights reserved.

Research paper thumbnail of Loss of Vascular Endothelial Growth Factor in Human Alopecia Hair Follicles

Journal of Investigative Dermatology, 1995

hair, whereas subsequent generations of hair have difficulty forming because the follicles are di... more hair, whereas subsequent generations of hair have difficulty forming because the follicles are distorted and the distal end can become separated from the rest of the follicle [5]. Skin samples were obtained from the dorsal region of hairless mutant mice and unaffected littermates; the samples were fixed and paraffin embedded. Tissue sections (5 /Lm) were deparaffinized, then probed with a polyclonal antibody against FGF-2 (a kind gifr of Dr. M.

Research paper thumbnail of Stromal cell-derived factor-1 mediates stem cell homing and tissue regeneration

Discovery medicine, 2003

Extract: The search for alternative treatments for congestive heart failure remains an ongoing ve... more Extract: The search for alternative treatments for congestive heart failure remains an ongoing venture. Exciting research over the last 2 years has changed the long held dogma that the heart cannot regenerate itself. The work of many groups can be summarized by the following concept: increasing the number of CD117+ (c-kit+) stem cells in cardiac tissue or in the coronary circulation within 2 days of a myocardial infarction results in regeneration of myocardial tissue and improved cardiac function. Animal studies by Orlic, Anversa and colleagues have demonstrated that either the direct injection of bone marrow-derived CD117+ stem cells in the infarct border zone at the time of myocardial infarction, or mobilization of these stem cells prior to myocardial infarction results in regeneration of cardiac myocytes and improved left ventricular (LV) function. In a critical experiment, Itescu and colleagues extended the window of therapeutic opportunity by demonstrating that the intravenous ...

Research paper thumbnail of dilated ischemic cardiomyopathy factor results in improved left ventricular function and neovascularization in Cellular, but not direct, adenoviral delivery of vascular endothelial growth

We sought to compare the effects on angiogenesis and left ventricular (LV) function of adenoviral... more We sought to compare the effects on angiogenesis and left ventricular (LV) function of adenoviral vascular endothelial growth factor-165 (AdVEGF-165) gene delivery by direct injection of AdVEGF-165 to the transplantation of skeletal myoblasts (SKMB) transfected with AdVEGF-165 in a rat model of ischemic cardiomyopathy. BACKGROUND Angiogenesis offers the potential for treating ischemic cardiomyopathy. However, the optimal method of delivering angiogenic factors for neovascularization remains undetermined. With the increased clinical interest in cell therapy for the treatment of LV dysfunction, SKMB transplantation may serve as a means of gene transfer. METHODS Two months after left anterior descending coronary artery ligation, rats received either injection of an adenoviral construct encoding VEGF-165, or 1 million SKMB transfected with AdLuciferase (AdLuc) or AdVEGF-165. Cardiac function was assessed echocardiographically, and neovascularization was assessed histologically four weeks after therapy. RESULTS Neovascularization was significantly increased by both AdVEGF delivery strategies (100 Ϯ 7% and 185 Ϯ 33% increase in vascular density compared with SKMB alone, respectively). However, cell-based delivery, but not direct injection of AdVEGF-165, resulted in increased cardiac function (73.5 Ϯ 12.6% and 1.5 Ϯ 8.8% increase in shortening fraction compared with saline control; AdLuc-transfected SKMB: 29.4 Ϯ 15.0%). The improved function was not due to increased engraftment of VEGF expressing SKMB. Rather, improved function correlated with less apoptosis in the border zone in those animals that received AdVEGF-165 expressing SKMB. CONCLUSION Our data demonstrate that cell-based delivery of VEGF leads to an improved treatment effect over direct adenoviral injection, and suggest that already developed adenoviral vectors that encode secreted factors could potentially offer greater efficacy in combination with SKMB transplantation.

Research paper thumbnail of CT angiography of the lower extremity circulation with protocols

Practical Approach with Clinical Protocols, 2007

Invasive digital subtraction angiography is the traditional method by which disease of the lower ... more Invasive digital subtraction angiography is the traditional method by which disease of the lower extremities has been assessed, but it is an expensive and time-consuming procedure with a complication rate of approximately 2–3%. To avoid unnecessary invasive diagnostic ...

Research paper thumbnail of What's Calcium's role in heart and kidney disease?

Research paper thumbnail of Targeted gene delivery to Kaposi's sarcoma cells via the fibroblast growth factor receptor

Cancer research, Jan 15, 1997

Kaposi's sarcoma (KS) is a major AIDS-related malignancy associated with significant morbidit... more Kaposi's sarcoma (KS) is a major AIDS-related malignancy associated with significant morbidity and mortality. Current chemotherapeutic regimens are associated with a dismal prognosis. In an effort to develop a new approach to KS treatment, we devised a gene therapy-based adenovirus retargeting schema that redirects the adenovirus to fibroblast growth factor receptors endogenously present on the cell surface of KS cells. By using a bifunctional conjugate consisting of a blocking antiadenoviral knob Fab linked to basic fibroblast growth factor, FGF2, the gene transduction of KS cells was enhanced 7.7-44 fold; recombinant adenoviruses encoding either the firefly luciferase reporter gene, or the herpes simplex thymidine kinase gene, demonstrated quantitative enhancement of expression in the KS cell lines. In this regard, two KS cell lines that were previously refractory to native adenovirus transduction could be successfully transduced by the addition of the conjugate. This study th...