Browsing by Author "Panitch, Alyssa"

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    Decorin Mimic Inhibits Vascular Smooth Muscle Proliferation and Migration
    (Public Library of Science, 2013-11-22) Scott, Rebecca A.; Paderi, John E.; Sturek, Michael; Panitch, Alyssa; Cellular and Integrative Physiology, School of Medicine
    Over the past 10 years, the number of percutaneous coronary intervention procedures performed in the United States increased by 33%; however, restenosis, which inhibits complete functional recovery of the vessel wall, complicates this procedure. A wide range of anti-restenotic therapeutics have been developed, although many elicit non-specific effects that compromise vessel healing. Drawing inspiration from biologically-relevant molecules, our lab developed a mimic of the natural proteoglycan decorin, termed DS-SILY, which can mask exposed collagen and thereby effectively decrease platelet activation, thus contributing to suppression of vascular intimal hyperplasia. Here, we characterize the effects of DS-SILY on both proliferative and quiescent human SMCs to evaluate the potential impact of DS-SILY-SMC interaction on restenosis, and further characterize in vivo platelet interactions. DS-SILY decreased proliferative SMC proliferation and pro-inflammatory cytokine secretion in vitro in a concentration dependent manner as compared to untreated controls. The addition of DS-SILY to in vitro SMC cultures decreased SMC migration and protein synthesis by 95% and 37%, respectively. Furthermore, DS-SILY decreased platelet activation, as well as reduced neointimal hyperplasia by 60%, in vivo using Ossabaw swine. These results indicate that DS-SILY demonstrates multiple biological activities that may all synergistically contribute to an improved treatment paradigm for balloon angioplasty.
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    Development of a Glycosaminoglycan Derived, Selectin Targeting Anti-Adhesive Coating to Treat Endothelial Cell Dysfunction
    (MDPI, 2017-03-29) Wodicka, James R.; Chambers, Andrea M.; Sangha, Gurneet S.; Goergen, Craig J.; Panitch, Alyssa; Medicine, School of Medicine
    Endothelial cell (EC) dysfunction is associated with many disease states including deep vein thrombosis (DVT), chronic kidney disease, sepsis and diabetes. Loss of the glycocalyx, a thin glycosaminoglycan (GAG)-rich layer on the EC surface, is a key feature of endothelial dysfunction and increases exposure of EC adhesion molecules such as selectins, which are involved in platelet binding to ECs. Once bound, platelets cause thrombus formation and an increased inflammatory response. We have developed a GAG derived, selectin targeting anti-adhesive coating (termed EC-SEAL) consisting of a dermatan sulfate backbone and multiple selectin-binding peptides designed to bind to inflamed endothelium and prevent platelet binding to create a more quiescent endothelial state. Multiple EC-SEAL variants were evaluated and the lead variant was found to preferentially bind to selectin-expressing ECs and smooth muscle cells (SMCs) and inhibit platelet binding and activation in a dose-dependent manner. In an in vivo model of DVT, treatment with the lead variant resulted in reduced thrombus formation. These results indicate that EC-SEAL has promise as a potential therapeutic in the treatment of endothelial dysfunction.
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    Proangiogenic Collagen-Binding Glycan Therapeutic Promotes Endothelial Cell Angiogenesis
    (American Chemical Society, 2021) Walimbe, Tanaya; Dehghani, Tima; Casella, Alena; Lin, Jenny; Wang, Aijun; Panitch, Alyssa; Surgery, School of Medicine
    Peripheral artery disease and endothelial cell dysfunction due to diabetes contribute to impaired neovascularization and poor healing of ischemic wounds. Treatments addressing this underlying ischemia that remain effective in the highly proteolytic diabetic wound environment are urgently needed to increase the rate of wound healing and reduce diabetes-related lower-limb amputations. Our lab has previously designed a collagen-targeted glycan therapeutic (DS-SILY) capable of protecting collagen-based scaffolds from matrix metalloproteinase (MMP) mediated degradation. Building upon this targeted technology, we designed the next generation glycan therapy, termed LXW7-DS-SILY (LDS), to also contain proangiogenic capabilities. By exploiting αvβ3 integrin-mediated VEGF signaling using our previously identified αvβ3 integrin targeted peptide (LXW7), we propose an alternative strategy to overcome shortcomings of traditional growth factor therapy. In this study, we describe the synthesis and optimization of LDS variants and evaluate their angiogenic potential in vitro and in vivo. LDS displayed binding to collagen and endothelial cells. In vitro, the LDS variant with 6 LXW7 peptides increased endothelial cell proliferation, migration, and tubule formation through increased VEGFR2 phosphorylation compared to non-treated controls. In vivo in a chick chorioallantoic membrane (CAM) assay, LDS laden collagen hydrogels increased blood vessel formation by 43% in comparison to organism matched blank hydrogels. Overall, these findings demonstrate the potential of a robust proangiogenic targeted therapeutic for the treatment of ischemic diabetic wounds.