mCRP triggers angiogenesis by inducing F3 transcription and TF signalling in microvascular endothelial cells

© Schattauer 2017. Inflammation contributes to vascular disease progression. However, the role of circulating inflammatory molecules on microvascular endothelial cell (mECs) is not fully elucidated. The aim of this study was to investigate the effects of the short pentraxin CRP on microvascular endothelial cell angiogenic function. Subcutaneously implanted collagen plugs seeded with human mECs exposed to monomeric CRP (mCRP) in mice showed formation of an extended network of microvessels both in the plug and the overlying skin tissue, while mECs exposure to pentameric native CRP (nCRP) induced a much milder effect. To understand the mechanisms behind this angiogenic effects, mECs were exposed to both CRP forms and cell migration, wound repair and tube-like formation were investigated. nCRP effects were moderate and of slow-onset whereas mCRP induced rapid, and highly significant effects. We investigated how circulating nCRP is transformed into mCRP by confocal microscopy and western blot. nCRP is transformed into mCRP on the mECs membranes in a time dependent fashion. This transformation is specific and in part receptor dependent, and the formed mCRP triggers F3 gene transcription and TF-protein expression in mECs to induce angiogenesis. F3-silenced mECs are unable to form angiotubes. In agreement, mCRP induced upregulation of the TF signalling pathway in mECs with downstream phosphorylation of AKT and activation of the transcription factor ETS1 leading to increased CCL2 release. The circulating pentraxin nCRP with little pro-angiogenic effect when dissociated into mCRP on the surface of mECs is able to trigger potent proangiogenic effects by inducing F3-gene upregulation and TF signalling

Properties and units in the clinical laboratory sciences part XXIV. Properties and units in clinical molecular genetics (IUPAC Technical Report)

Molecular Technology and Informatics for Personalised Medicine and Healt

Poly(ethylmethacrylate-co-diethylaminoethyl acrylate) coating improves endothelial re-population, bio-mechanical and anti-thrombogenic properties of decellularized carotid arteries for blood vessel replacement

Decellularized vascular scaffolds are promising materials for vessel replacements. However, despite the natural origin of decellularized vessels, issues such as biomechanical incompatibility, immunogenicity risks and the hazards of thrombus formation, still need to be addressed. In this study, we coated decellularized vessels obtained from porcine carotid arteries with poly (ethylmethacrylate-co-diethylaminoethylacrylate) (8g7) with the purpose of improving endothelial coverage and minimizing platelet attachment while enhancing the mechanical properties of the decellularized vascular scaffolds. The polymer facilitated binding of endothelial cells (ECs) with high affinity and also induced endothelial cell capillary tube formation. In addition, platelets showed reduced adhesion on the polymer under flow conditions. Moreover, the coating of the decellularized arteries improved biomechanical properties by increasing its tensile strength and load. In addition, after 5 days in culture, ECs seeded on the luminal surface of 8g7-coated decellularized arteries showed good regeneration of the endothelium. Overall, this study shows that polymer coating of decellularized vessels provides a new strategy to improve re-endothelialization of vascular grafts, maintaining or enhancing mechanical properties while reducing the risk of thrombogenesis. These results could have potential applications in improving tissue-engineered vascular grafts for cardiovascular therapies with small caliber vessels

Monocyte chemoattractant protein-1/CCL2 produced by stromal cells promotes lung metastasis of 4T1 murine breast cancer cells

MCP-1/CCL2 plays an important role in the initiation and progression of cancer. Since tumor cells produce MCP-1, they are considered to be the main source of this chemokine. Here, we examined whether MCP-1 produced by non-tumor cells affects the growth and lung metastasis of 4T1 breast cancer cells by transplanting them into the mammary pad of WT or MCP-1−/− mice. Primary tumors at the injected site grew similarly in both mice; however, lung metastases were markedly reduced in MCP-1−/− mice, with significantly longer mouse survival. High levels of MCP-1 mRNA were detected in tumors growing in WT, but not MCP-1−/− mice. Serum MCP-1 levels were increased in tumor-bearing WT, but not MCP-1−/− mice. Transplantation of MCP-1−/− bone marrow cells into WT mice did not alter the incidence of lung metastasis, whereas transplantation of WT bone marrow cells into MCP-1−/− mice increased lung metastasis. The primary tumors of MCP-1−/− mice consistently developed necrosis earlier than those of WT mice and showed decreased infiltration by macrophages and reduced angiogenesis. Interestingly, 4T1 cells that metastasized to the lung constitutively expressed elevated levels of MCP-1, and intravenous injection of 4T1 cells producing a high level of MCP-1 resulted in increased tumor foci in the lung of WT and MCP-1−/− mice. Thus, stromal cell-derived MCP-1 in the primary tumors promotes lung metastasis of 4T1 cells, but tumor cell-derived MCP-1 can also contribute once tumor cells enter the circulation. A greater understanding of the source and role of this chemokine may lead to novel strategies for cancer treatment