Receptor protein tyrosine phosphatase beta/zeta (RPTPβ/ζ) is a chondroitin sulphate (CS) transmembrane protein tyrosine phosphatase and is a receptor for pleiotrophin (PTN). RPTPβ/ζ interacts with ανβ3 on the cell surface and upon binding of PTN leads to c-Src dephosphorylation at Tyr530, β3 Tyr773 phosphorylation, cell surface nucleolin (NCL) localization and stimulation of cell migration. c-Src-mediated β3 Tyr773 phosphorylation is also observed after vascular endothelial growth factor 165 (VEGF165) stimulation of endothelial cells and is essential for VEGF receptor type 2 (VEGFR2) - ανβ3 integrin association and subsequent signaling. In the present work, we studied whether RPTPβ/ζ mediates angiogenic actions of VEGF. Human umbilical vein endothelial, human glioma U87MG and stably transfected Chinese hamster ovary cells expressing different β3 subunits were used. Protein-protein interactions were studied by a combination of immunoprecipitation/Western blot, immunofluorescence and proximity ligation assays, properly quantified as needed. RPTPβ/ζ expression was down-regulated using small interference RNA technology. Migration assays were performed in 24-well microchemotaxis chambers, using uncoated polycarbonate membranes with 8 μm pores. RPTPβ/ζ mediates VEGF165-induced c-Src-dependent β3 Tyr773 phosphorylation, which is required for VEGFR2-ανβ3 interaction and the downstream activation of phosphatidylinositol 3-kinase (PI3K) and cell surface NCL localization. RPTPβ/ζ directly interacts with VEGF165, and this interaction is not affected by bevacizumab, while it is interrupted by both CS-E and PTN. Down-regulation of RPTPβ/ζ by siRNA or administration of exogenous CS-E abolishes VEGF165-induced endothelial cell migration, while PTN inhibits the migratory effect of VEGF165 to the levels of its own effect. These data identify RPTPβ/ζ as a cell membrane binding partner for VEGF that regulates angiogenic functions of endothelial cells and suggest that it warrants further validation as a potential target for development of additive or alternative anti-VEGF therapies.

A thirty-year-old pregnant woman was admitted to hospital with headache and gastrointestinal discomfort. She developed peripheral oedema and had an emergency caesarean section following an episode of tonic-clonic seizures. Her delivery was further complicated by postpartum haemorrhage and she was admitted to the Intensive Care Unit (ICU) for further resuscitation and seizure control which required infusions of magnesium and multiple anticonvulsants. Despite haemodynamic optimisation she developed an acute kidney injury with evidence of liver damage, thrombocytopenia and haemolysis. Haemolysis, Elevated Liver enzymes and Low Platelets (HELLP) syndrome, a multisystem disease of advanced pregnancy which overlaps with pre-eclampsia, was diagnosed. HELLP syndrome is associated with a range of complications which may require critical care support, including placental abruption and foetal loss, acute kidney injury, microangiopathic haemolytic anaemia, acute liver failure and liver capsule rupture. Definitive treatment of HELLP is delivery of the fetus and in its most severe forms requires admission to the ICU for multiorgan support. Therapeutic strategies in ICU are mainly supportive and include blood pressure control, meticulous fluid balance and possibly escalation to renal replacement therapy, mechanical ventilation, neuroprotection, seizure control, and management of liver failure-related complications. Multidisciplinary input is essential for optimal treatment.

The aim of this study was to demonstrate a percutaneous transauricular method of balloon angioplasty in high-cholesterol fed rabbits, as an innovative atherosclerosis model. Twenty male New Zealand rabbits were randomly divided into two groups of ten animals, as follows: atherogenic diet plus balloon angioplasty (group A) and atherogenic diet alone (group B). Balloon angioplasty was performed in the descending thoracic aorta through percutaneous catheterization of the auricular artery. Eight additional animals fed regular diet were served as long term control. At the end of 9 week period, rabbits were euthanized and thoracic aortas were isolated for histological, immunohistochemical and biochemical analysis. Atherogenic diet induced severe hypercholesterolemia in both group A and B (2802 ± 188.59 and 4423 ± 493.39 mg/dl respectively) compared to the control animals (55.5 ± 11.82 mg/dl; P < 0.001). Group A atherosclerotic lesions appeared to be more advanced histologically (20% type IV and 80% type V) compared to group B lesions (50% type III and 50% type IV). Group A compared to group B atherosclerotic lesions demonstrated similar percentage of macrophages (79.5 ± 9.56% versus 84 ± 12.2%; P = 0.869), more smooth muscle cells (61 ± 14.10% versus 40.5 ± 17.07; P = 0.027), increased intima/media ratio (1.20 ± 0.50 versus 0.62 ± 0.13; P = 0.015) despite the similar degree of intimal hyperplasia (9768 ± 1826.79 μm² versus 12205 ± 8789.23 μm²; P = 0.796), and further significant lumen deterioration (23722 ± 4508.11 versus 41967 ± 20344.61 μm²; P = 0.05) and total vessel area reduction (42350 ± 5819.70 versus 73190 ± 38902.79 μm²; P = 0.022). Group A and B animals revealed similar nitrated protein percentage (P = NS), but significantly higher protein nitration compared to control group (P < 0.01; P < 0.01, respectively). No deaths or systemic complications were reported. Transauricular balloon angioplasty constitutes a safe, minimally invasive and highly successful model of induced atherosclerosis in hyperlipidaemic rabbits.

Background/Objectives: In the tumor microenvironment, hypoxia regulates genes that support tumor cell invasion and angiogenesis under the control of the hypoxia-inducible transcription factors (HIFs). Pleiotrophin (PTN) is a secreted protein that activates cell migration in endothelial and cancer cells that express α_νβ₃ integrin but has inhibitory effects in cells that do not express α_νβ₃ integrin. In both cases, the protein tyrosine phosphatase receptor zeta 1 (PTPRZ1) seems to mediate the effects of PTN. In the present work, we studied the effect of hypoxia on PTN and PTPRZ1 expression and the functional consequences of this effect. Methods: Western blot, quantitative real-time PCR, and luciferase assays were used to study the impact of hypoxia at the protein, mRNA, and transcriptional levels, respectively. Decoy oligonucleotides (ODNs), siRNA technology, and plasmid overexpression were used to study the involvement of the transcription factors studied. Functional assays were used to study the effect of hypoxia on cell proliferation and migration. Results: Hypoxia increases PTN expression through the transcriptional activation of the corresponding gene in α_νβ₃ integrin-expressing cells. The transcription factors HIF-1α, HIF-2α, and AP-1 mediate the up-regulation of PTN by hypoxia. Functional assays in endothelial cells from PTN knockout mice or endothelial and cancer cells following the downregulation of PTN expression showed that PTN negatively affects chemical hypoxia-induced cell proliferation and migration. In cancer cells that do not express α_νβ₃ integrin, hypoxia or chemical hypoxia inhibits PTN expression in a HIF-1α-, HIF-2α-, and AP-1-independent manner. The expression of PTPRZ1 is up-regulated by chemical hypoxia, is HIF-1α- and HIF-2α-dependent, and seems to limit the activation of HIF-1α, at least in endothelial cells. Conclusions: Hypoxia or chemical hypoxia regulates PTN and PTPRZ1 expressions to restrict the stimulatory effects of hypoxia on endothelial and cancer cell migration.