Browsing by Subject "neovascularization"

Now showing 1 - 4 of 4
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    Angiogenesis: A Cellular Response to Traumatic Injury
    (Wolters Kluwer, 2020) Pecoraro, Anthony R.; Hosfield, Brian D.; Li, Hongge; Shelley, W. Christopher; Markel, Troy A.; Surgery, School of Medicine
    The development of new vasculature plays a significant role in a number of chronic disease states, including neoplasm growth, peripheral arterial disease, and coronary artery disease, among many others. Traumatic injury and hemorrhage, however, is an immediate, often dramatic pathophysiologic insult which can also necessitate neovascularization to promote healing. Traditional understanding of angiogenesis involved resident endothelial cells branching outward from localized niches in the periphery. Additionally, there are a small number of circulating endothelial progenitor cells which participate directly in the process of neovessel formation. The bone marrow stores a relatively small number of so-called pro-angiogenic hematopoietic progenitor cells (PACs) – that is, progenitor cells of a hematopoietic potential that differentiate into key structural cells and stimulate or otherwise support local cell growth/differentiation at the site of angiogenesis. Following injury, a number of cytokines and intercellular processes are activated or modulated to promote development of new vasculature. These processes initiate and maintain a robust response to vascular insult, allowing new vessels to canalize and anastomose and provide timely oxygen delivering to healing tissue. Ultimately as we better understand the key players in the process of angiogenesis we can look to develop novel techniques to promote healing following injury.
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    Elucidating the Role of Ref-1 in Retinal Neovascularization
    (2025-05) Hartman, Gabriella D.; Yoder, Karmen K.; Corson, Timothy W.; Kelley, Mark R.; Fishel, Melissa L.; Pattabiraman, Padmanabhan
    Retinal neovascularization in retinopathy of prematurity (ROP) and proliferative diabetic retinopathy (PDR) impairs vision. Current treatments of intravitreal (IVT) antivascular endothelial growth factor (VEGF) injections are accompanied by high treatment burden and resistance. Also, VEGF alone is not sufficient for induction of neovascularization, suggesting that targeting multiple disease-relevant pathways may increase therapeutic response. Thus, there is a critical need to develop novel therapies that modulate multiple disease-relevant pathways. APE1/Ref-1, a multifunctional protein with both endonuclease (APE1) and redox regulatory activity (Ref-1), activates multiple transcription factors linked to retinal neovascularization. However, the precise molecular mechanisms of Ref-1 in retinal neovascularization remain unclear. To investigate this, I examined the expression of Ref- 1 in two mouse models of retinal neovascularization – the oxygen-induced retinopathy (OIR) and the Vldlr-/- model – and observed elevated Ref-1 expression at sites of neovascularization. Further, I observed heightened expression of Ref-1 in endothelial cells in human PDR tissue compared to normal eyes. Through cell-based and biochemical approaches, I identified that Ref-1 redox activity modulates canonical Wnt signaling, and inhibition of Ref-1 redox activity blocks Wnt signaling activation. I found that Ref-1 redox activity regulates HIF-1a transcriptional activation in hypoxic human retinal endothelial cells. Hypoxia-induced activation of Wnt signaling was regulated by Ref-1, suggesting a dynamic Ref-1-HIF-1a-Wnt signaling axis. Finally, inhibition of Ref-1 redox activity decreased retinal neovascularization and downregulated expression of Wnt- and angiogenesis-related genes at sites of neovascularization in a mouse model of retinal neovascularization. These findings suggest that Ref-1 redox activity promotes ischemic retinal neovascularization via Wnt signaling activation. This study advanced our understanding of Ref-1’s role in neovascular eye diseases, and targeting Ref-1 with a redox inhibitor could offer a novel therapeutic strategy for retinal neovascularization.
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    Hepatocyte growth factor regulates neovascularization in developing fat pads
    (American Physiological Society (APS), 2014-01-15) White, Heather M.; Acton, Anthony J.; Kamocka, Malgorzata M.; Considine, Robert V.; Department of Medicine, IU School of Medicine
    In this study, we used lentiviral-delivered shRNA to generate a clonal line of 3T3-F442A preadipocytes with stable silencing of hepatocyte growth factor (HGF) expression and examined the long-term consequence of this modification on fat pad development. HGF mRNA expression was reduced 94%, and HGF secretion 79% (P < 0.01), compared with preadipocytes treated with nontargeting shRNA. Fat pads derived from HGF knockdown preadipocytes were significantly smaller (P < 0.01) than control pads beginning at 3 days postinjection (0.022 ± 0.003 vs. 0.037 ± 0.004 g), and further decreased in size at day 7 (0.015 ± 0.004 vs. 0.037 ± 0.003 g) and day 14 (0.008 ± 0.002 vs. 0.045 ± 0.007 g). Expression of the endothelial cell genes TIE1 and PECAM1 increased over time in control fat pads (1.6 ± 0.4 vs. 11.4 ± 1.7 relative units at day 3 and 14, respectively; P < 0.05) but not in HGF knockdown fat pads (1.1 ± 0.5 vs. 5.9 ± 2.2 relative units at day 3 and 14). Contiguous vascular structures were observed in control fat pads but were much less developed in HGF knockdown fat pads. Differentiation of preadipocytes to mature adipocytes was significantly attenuated in HGF knockdown fat pads. Fat pads derived from preadipocytes with knockdown of the HGF receptor c-MET were smaller than control pads at day 3 postinjection (0.034 ± 0.002 vs. 0.049 ± 0.004 g; P < 0.05), and remained the same size through day 14. c-MET knockdown fat pads developed a robust vasculature, and preadipocytes differentiated to mature adipocytes. Overall these data suggest that preadipocyte-secreted HGF is an important regulator of neovascularization in developing fat pads.
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    Small-molecule inhibitors of ferrochelatase are antiangiogenic agents
    (Elsevier, 2022-01-31) Sishtla, Kamakshi; Lambert-Cheatham, Nathan; Lee, Bit; Han, Duk Hee; Park, Jaehui; Sardar Pasha, Sheik Pran Babu; Lee, Sanha; Kwon, Sangil; Muniyandi, Anbukkarasi; Park, Bomina; Odell, Noa; Waller, Sydney; Park, Il Yeong; Lee, Soo Jae; Seo, Seung-Yong; Corson, Timothy W.; Ophthalmology, School of Medicine
    Activity of the heme synthesis enzyme ferrochelatase (FECH) is implicated in multiple diseases. In particular, it is a mediator of neovascularization in the eye and thus an appealing therapeutic target for preventing blindness. However, no drug-like direct FECH inhibitors are known. Here, we set out to identify small-molecule inhibitors of FECH as potential therapeutic leads using a high-throughput screening approach to identify potent inhibitors of FECH activity. A structure-activity relationship study of a class of triazolopyrimidinone hits yielded drug-like FECH inhibitors. These compounds inhibit FECH in cells, bind the active site in cocrystal structures, and are antiangiogenic in multiple in vitro assays. One of these promising compounds was antiangiogenic in vivo in a mouse model of choroidal neovascularization. This foundational work may be the basis for new therapeutic agents to combat not only ocular neovascularization but also other diseases characterized by FECH activity.