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1.
Blood ; 134(17): 1469-1479, 2019 10 24.
Article in English | MEDLINE | ID: mdl-31501155

ABSTRACT

Fluid shear stress in the vasculature is the driving force for natural bypass growth, a fundamental endogenous mechanism to counteract the detrimental consequences of vascular occlusive disease, such as stroke or myocardial infarction. This process, referred to as "arteriogenesis," relies on local recruitment of leukocytes, which supply growth factors to preexisting collateral arterioles enabling them to grow. Although several mechanosensing proteins have been identified, the series of mechanotransduction events resulting in local leukocyte recruitment is not understood. In a mouse model of arteriogenesis (femoral artery ligation), we found that endothelial cells release RNA in response to increased fluid shear stress and that administration of RNase inhibitor blocking plasma RNases improved perfusion recovery. In contrast, treatment with bovine pancreatic RNase A or human recombinant RNase1 interfered with leukocyte recruitment and collateral artery growth. Our results indicated that extracellular RNA (eRNA) regulated leukocyte recruitment by engaging vascular endothelial growth factor receptor 2 (VEGFR2), which was confirmed by intravital microscopic studies in a murine cremaster model of inflammation. Moreover, we found that release of von Willebrand factor (VWF) as a result of shear stress is dependent on VEGFR2. Blocking VEGFR2, RNase application, or VWF deficiency interfered with platelet-neutrophil aggregate formation, which is essential for initiating the inflammatory process in arteriogenesis. Taken together, the results show that eRNA is released from endothelial cells in response to shear stress. We demonstrate this extracellular nucleic acid as a critical mediator of mechanotransduction by inducing the liberation of VWF, thereby initiating the multistep inflammatory process responsible for arteriogenesis.


Subject(s)
Endothelial Cells/metabolism , Mechanotransduction, Cellular , Neovascularization, Physiologic , RNA/metabolism , Stress, Mechanical , Animals , Arteries/physiology , Cattle , Cells, Cultured , Endothelial Cells/cytology , Mice , Mice, Inbred C57BL
2.
EBioMedicine ; 27: 237-246, 2018 Jan.
Article in English | MEDLINE | ID: mdl-29233575

ABSTRACT

Midkine is a pleiotropic factor, which is involved in angiogenesis. However, its mode of action in this process is still ill defined. The function of midkine in arteriogenesis, the growth of natural bypasses from pre-existing collateral arteries, compensating for the loss of an occluded artery has never been investigated. Arteriogenesis is an inflammatory process, which relies on the proliferation of endothelial cells and smooth muscle cells. We show that midkine deficiency strikingly interferes with the proliferation of endothelial cells in arteriogenesis, thereby interfering with the process of collateral artery growth. We identified midkine to be responsible for increased plasma levels of vascular endothelial growth factor A (VEGFA), necessary and sufficient to promote endothelial cell proliferation in growing collaterals. Mechanistically, we demonstrate that leukocyte domiciled midkine mediates increased plasma levels of VEGFA relevant for upregulation of endothelial nitric oxide synthase 1 and 3, necessary for proper endothelial cell proliferation, and that non-leukocyte domiciled midkine additionally improves vasodilation. The data provided on the role of midkine in endothelial proliferation are likely to be relevant for both, the process of arteriogenesis and angiogenesis. Moreover, our data might help to estimate the therapeutic effect of clinically applied VEGFA in patients with vascular occlusive diseases.


Subject(s)
Femoral Artery/growth & development , Femoral Artery/metabolism , Intercellular Signaling Peptides and Proteins/pharmacology , Nitric Oxide Synthase/metabolism , Organogenesis/drug effects , Vascular Endothelial Growth Factor A/metabolism , Animals , Biological Availability , Bone Marrow Cells/drug effects , Bone Marrow Cells/metabolism , Cell Proliferation/drug effects , Endothelial Cells/cytology , Endothelial Cells/drug effects , Endothelial Cells/metabolism , Femoral Artery/drug effects , Leukocytes/drug effects , Leukocytes/metabolism , Mice, Inbred C57BL , Midkine , Models, Biological , Nitroso Compounds/pharmacology
3.
Cell Rep ; 16(8): 2197-2207, 2016 08 23.
Article in English | MEDLINE | ID: mdl-27524614

ABSTRACT

The body has the capacity to compensate for an occluded artery by creating a natural bypass upon increased fluid shear stress. How this mechanical force is translated into collateral artery growth (arteriogenesis) is unresolved. We show that extravasation of neutrophils mediated by the platelet receptor GPIbα and uPA results in Nox2-derived reactive oxygen radicals, which activate perivascular mast cells. These c-kit(+)/CXCR-4(+) cells stimulate arteriogenesis by recruiting additional neutrophils as well as growth-promoting monocytes and T cells. Additionally, mast cells may directly contribute to vascular remodeling and vascular cell proliferation through increased MMP activity and by supplying growth-promoting factors. Boosting mast cell recruitment and activation effectively promotes arteriogenesis, thereby protecting tissue from severe ischemic damage. We thus find that perivascular mast cells are central regulators of shear stress-induced arteriogenesis by orchestrating leukocyte function and growth factor/cytokine release, thus providing a therapeutic target for treatment of vascular occlusive diseases.


Subject(s)
Endothelial Cells/metabolism , Mast Cells/metabolism , Mechanotransduction, Cellular , Neovascularization, Physiologic/genetics , Neutrophils/metabolism , Vascular Remodeling/genetics , Animals , Arteries/metabolism , Arteries/pathology , Blood Platelets/cytology , Blood Platelets/metabolism , Cell Proliferation , Endothelial Cells/cytology , Gene Expression Regulation , Hindlimb/blood supply , Intercellular Signaling Peptides and Proteins/genetics , Intercellular Signaling Peptides and Proteins/metabolism , Male , Mast Cells/cytology , Matrix Metalloproteinases/genetics , Matrix Metalloproteinases/metabolism , Mice , Monocytes/cytology , Monocytes/metabolism , NADPH Oxidase 2/genetics , NADPH Oxidase 2/metabolism , Neutrophils/cytology , Platelet Glycoprotein GPIb-IX Complex/genetics , Platelet Glycoprotein GPIb-IX Complex/metabolism , Proto-Oncogene Proteins c-kit/genetics , Proto-Oncogene Proteins c-kit/metabolism , Reactive Oxygen Species/metabolism , Receptors, CXCR4/genetics , Receptors, CXCR4/metabolism , Stress, Mechanical , T-Lymphocytes/cytology , T-Lymphocytes/metabolism , Urokinase-Type Plasminogen Activator/genetics , Urokinase-Type Plasminogen Activator/metabolism
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