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Browsing by Subject "Vascular injury"
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Item Direct Evidence for P2Y2 Receptor Involvement in Vascular Response to Injury(Karger Publishers, 2016) Agca, Yuksel; Qian, Shaomin; Agca, Cansu; Seye, Cheikh I.; Cellular and Integrative Physiology, School of MedicineObjectives Extracellular nucleotide release at the site of arterial injury mediates proliferation and migration of vascular smooth muscle cells (SMC). Our aim was to investigate the role of the P2Y2 nucleotide receptor (P2Y2R) in neointimal hyperplasia. Approach and Results Vascular injury was induced by implantation of a polyethylene cuff around the femoral artery in wild-type and P2Y2 receptor-deficient mice (P2Y2R−/−). Electron microscopy was used to analyze monocyte and lymphocyte influx to the intima 36 hours post-injury. Compared to wild-type (WT) littermates, P2Y2R−/− mice exhibited a 3-fold decreased number of mononuclear leukocytes invading the intima (p<0.05). Concomitantly, migration of smooth muscle cells was decreased by more than 60% (p<0.05) a resulting in a sharp inhibition of intimal thickening formation in P2Y2R−/− mice (n=15) 14 days after cuff placement. In vitro, loss of P2Y2 receptor significantly impaired monocyte migration in response to nucleotide agonists. Furthermore, transgenic rats over-expressing the P2Y2R developed accelerated intimal lesions resulting in more than 95% luminal stenosis (P<0.05, n=10). Conclusions Loss-and gain-of-function approaches established a direct evidence for P2Y2 receptor involvement in neointimal hyperplasia. Specific anti-P2Y2 receptor therapies may be used against restenosis and bypass graft failure.Item Identification of Key Determinants of Cerebral Malaria Development and Inhibition Pathways(American Society for Microbiology, 2022) Cha, Sung-Jae; Yu, Xiang; Gregory, Brian D.; Lee, Yong Seok; Ishino, Tomoko; Opoka, Robert O.; John, Chandy C.; Jacobs-Lorena, Marcelo; Pediatrics, School of MedicineCerebral malaria (CM), coma caused by Plasmodium falciparum-infected red blood cells (iRBCs), is the deadliest complication of malaria. The mechanisms that lead to CM development are incompletely understood. Here we report on the identification of activation and inhibition pathways leading to mouse CM with supporting evidence from the analysis of human specimens. We find that CM suppression can be induced by vascular injury when sporozoites exit the circulation to infect the liver and that CM suppression is mediated by the release of soluble factors into the circulation. Among these factors is insulin like growth factor 1 (IGF1), administration of which inhibits CM development in mice.