Tıp Fakültesi / Faculty of Medicine
Permanent URI for this collectionhttps://hdl.handle.net/11727/1403
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Item The Notch Pathway Is A Critical Regulator of Angiogenesis in A Skin Model of Ischemia(2015) Abbas, Ozan L.; Borman, Huseyin; Terzi, Yunus K.; Terzi, Aysen; Bayraktar, Nilufer; Yazici, Ayse C.; 0000-0002-1225-1320; 0000-0002-7886-3688; 0000-0001-5612-9696; 0000-0002-3132-242X; 25834117; F-7546-2013; Y-8758-2018; B-4372-2018; AAS-6810-2021The Notch pathway is definitely required for normal vascular development. Although the contribution of Notch in postnatal angiogenesis is the focus of intense investigation, the implication of Notch in reparative neovascularization in the skin remains unexplored. In this study, we investigated Notch changes using a skin model of ischemia. Thirty Sprague-Dawley rats were divided into two groups. In the surgery group (n = 24), a caudally based dorsal skin flap was raised and sutured back into its initial position. In the control group, no surgical procedure was performed. Tissue biopsies were obtained at different time intervals. Tissue specimens were assessed for Delta-like ligand 4 (DLL4) and vascular endothelial growth factor (VEGF) gene expression by real-time polymerase chain reaction (PCR). Immunohistochemical staining was used for detection of DLL4 in tissue materials. Quantitative assessment of skin flap microvasculature was made. Compared with normoperfused tissue, VEGF and DLL4 expressions increased significantly (p < 0.01). Immunohistochemical analysis revealed weak and patchy expression of DLL4 in microvascular endothelial cells of normoperfused tissues. Conversely, DLL4 expression was upregulated in capillary endothelial cells after ischemia. In conclusion, in this study we have shown that the Notch ligand DLL4 is upregulated in skin tissue after ischemia. A deeper understanding of these fundamental principles will aid in the development of new avenues for the treatment of blood vessel-related skin pathologies.Item Inhibition of the Notch Pathway Promotes Flap Survival by Inducing Functional Neoangiogenesis(2015) Abbas, Ozan Luay; Borman, Huseyin; Terzi, Yunus K.; Terzi, Aysen; Bayraktar, Nilufer; Ozkan, Burak; Yazici, Ayse C.; 0000-0002-7886-3688; 0000-0003-3093-8369; 0000-0002-1225-1320; 0000-0002-3132-242X; 0000-0001-5612-9696; 25180956; Y-8758-2018; AAI-5063-2020; F-7546-2013; AAS-6810-2021; B-4372-2018Objective The Notch pathway seems to function as an antiangiogenic factor, negatively regulating the sprouting effect of vascular endothelial growth factor (VEGF). This function is well defined in embryonic and tumor vasculature. However, little is known about its function in ischemia-induced angiogenesis. In the first part of this study, we investigated the role of Notch in reparative angiogenesis after ischemia. In the second part, we hypothesized that anti-Notch therapy will result in increased angiogenic sprouting. We analyzed the effect of Notch inhibition in the induction of angiogenic sprouting. Methods In the first part, we investigated the effect of ischemia on the Notch ligand delta-like ligand 4 (DLL4). Twenty rats were divided equally into 2 groups. In the surgery group, dorsal skin flap was used as model of ischemia. In the control group, no surgical procedure was performed. DLL4 and VEGF gene expressions were assessed. Immunohistochemical staining was used for detection of DLL4 in tissue materials. Plasma levels of VEGF and DLL4 were measured. In the second part, we investigated the effect of Notch inhibition using a gamma-secretase inhibitor (GSI) on inducing neoangiogenesis. Twenty rats were assigned to 2 equal groups. In all animals, dorsal skin flap was raised and sutured back into its bed. Animals in the GSI-treated group received GSI intravenously after surgery for 3 days. Saline was administered in the control group. Necrotic area measurements, microangiography, and histologic evaluations were performed to compare groups. Results In the first part, VEGF and DLL expressions increased in ischemic tissues (P < 0.01). Immunohistochemical analysis revealed that DLL4 expression was upregulated in capillary endothelial cells after ischemia. Plasma levels for VEGF and DLL4 were higher in the animals that underwent surgery (P < 0.01). In the second part, GSI treatment resulted in higher flap survival rates (P < 0.05). Microscopic analysis exhibited increase in the number of microvascular structures after GSI treatment (P < 0.05). Microangiographic evaluation showed that neovascularization increased in the GSI-applied flaps. Conclusions We present an evidence for the importance of the Notch pathway in the regulation of ischemia-induced angiogenesis. Notch inhibition promotes flap survival by creating a neovasculature that has an increase in vascular density.Item Increased Expression of Nestin and VEGF in Endometrial Polyps: An Immunhistochemical Study(2016) Erinanc, Hilal; Toprak, Erzat; 0000-0003-1401-6356; 0000-0002-2877-1232; AAL-1268-2021; ABI-5902-2020; GRR-9885-2022Background: Pathogenesis of endometrial polyps have not been fully understood however the increased proliferation of blood vessells and fibrosis may play an important role in the pathogenesis of endometrial polyps. Vascular endothelial growth factor (VEGF) is a a key regulator of angiogenesis and vascular function. Nestin is another molecule which has been reported to be associated with the process of angiogenesis. The aim of this study was to evaluate the expression of Nestin protein and VEGF in pathogenesis of endometrial polyps. Methods: A total of 20 women who had hysteroscopic and histologic confirmation of benign endometrial polyps and their normal endometrial tissue were recruited into the study. Immunohistochemical analysis for VEGF, Nestin and CD34 were performed on formalin fixed, paraffin-embedded tissue using the streptavidin-biotin-peroxidase technique. Angiogenesis was assessed by immunohistochemistry using monoclonal antibody against CD34. Results: Immunostaining of VEGF in glandular epithelial cells and stromal fibroblasts, and immunostaining of Nestin in newly formed vessels were determined. Immunopositivity staining of VEGF in endometrial polyps were significantly stronger than normal endometrium (P<0.05). Nestin expression was observed in vessels which were smaller than that of CD34-positive preexisting large blood vessels. Endometrial polyps demonstrated significantly greater expression of Nestin in proliferating endothelial cells, compared with control endometrium (P<0.05). Conclusion: This study suggests that the increased expression of VEGF and Nestin protein which are may have a role in the pathogenesis of endometrial polyps.Item Enhancement of Vascular Endothelial Growth Factor's Angiogenic Capacity by the Therapeutic Modulation of Notch Signalling Improves Tram Flap Survival in Rats Submitted to Nicotine(2017) Abbas, Ozan Luay; Terzi, Yunus Kasim; Ozatik, Orhan; Ozatik, Fikriye Yasemin; Turna, Gamze; Nar, Rukiye; Musmul, Ahmet; 0000-0001-5612-9696; 0000-0002-4662-6493; 0000-0002-8422-2975; 28277073; B-4372-2018; GXA-2381-2022; HOH-8201-2023Background: Smoke of cigarettes, and specifically nicotine, has been shown to diminish pedicled transverse rectus abdominis musculocutaneous (TRAM) flap survival. Considering that Notch signalling through its ligand Delta-like 4 (Dll4) functions as anti-angiogenic factor by inhibiting the pro-angiogenic effects of vascular endothelial growth factor (VEGF), it is hypothesised that inhibition of the Notch would promote angiogenesis and increase TRAM flap survival in rats submitted to nicotine. Methods: Twenty rats were treated with nicotine for 28 days preoperatively. Thereafter, a pedicled TRAM flap was created in all animals. The Notch inhibitor N-[N-(3,5-difluorophenacetyl)-1-alanyl]-S-phenylglycine-t-butyl-ester was administered in animals of the treatment group. Animals in the control group were given the same amount of solvent. Five days after the surgery, viable flap areas were determined. Skin samples were evaluated for VEGF and Dll4 mRNA levels. Immunohistochemical analysis was used for the assessment of endothelial Dll4 expression. Vascular density was determined histologically. Plasma levels of VEGF and Dll4 were measured. Results: A significant improvement in TRAM flap surviving area was observed in the treatment group (53.5014.25%) compared with the controls (32.20 +/- 9.15%). Immunohistochemical analysis revealed a significant increase in the number of Dll4 stained vessels in animals of the treatment group (9.2 +/- 1.6) in comparison with the controls (5.7 +/- 1.9). VEGF mRNA levels (0.22 +/- 0.08) in the treatment group were significantly lower than those in the control group (0.36 +/- 0.09). Conclusion: Notch inhibition significantly improved TRAM flap survival in animals exposed to nicotine by promoting VEGF-induced angiogenesis.