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      ProNGF, a cytokine induced after myocardial infarction in humans, targets pericytes to promote microvascular damage and activation

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          Abstract

          proNGF and p75NTR are induced following fatal myocardial infraction and are required for the development of microvascular injury.

          Abstract

          Treatment of acute cardiac ischemia focuses on reestablishment of blood flow in coronary arteries. However, impaired microvascular perfusion damages peri-infarct tissue, despite arterial patency. Identification of cytokines that induce microvascular dysfunction would provide new targets to limit microvascular damage. Pro–nerve growth factor (NGF), the precursor of NGF, is a well characterized cytokine in the brain induced by injury. ProNGF activates p75 neurotrophin receptor (p75 NTR) and sortilin receptors to mediate proapoptotic responses. We describe induction of proNGF by cardiomyocytes, and p75 NTR in human arterioles after fatal myocardial infarction, but not with unrelated pathologies. After mouse cardiac ischemia-reperfusion (I-R) injury, rapid up-regulation of proNGF by cardiomyocytes and p75 NTR by microvascular pericytes is observed. To identify proNGF actions, we generated a mouse expressing a mutant Ngf allele with impaired processing of proNGF to mature NGF. The proNGF-expressing mouse exhibits cardiac microvascular endothelial activation, a decrease in pericyte process length, and increased vascular permeability, leading to lethal cardiomyopathy in adulthood. Deletion of p75 NTR in proNGF-expressing mice rescues the phenotype, confirming the importance of p75 NTR-expressing pericytes in the development of microvascular injury. Furthermore, deficiency in p75 NTR limits infarct size after I-R. These studies identify novel, nonneuronal actions for proNGF and suggest that proNGF represents a new target to limit microvascular dysfunction.

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          Most cited references 62

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          Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm.

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            Neurotrophin-regulated signalling pathways.

             L F Reichardt (2006)
            Neurotrophins are a family of closely related proteins that were identified initially as survival factors for sensory and sympathetic neurons, and have since been shown to control many aspects of survival, development and function of neurons in both the peripheral and the central nervous systems. Each of the four mammalian neurotrophins has been shown to activate one or more of the three members of the tropomyosin-related kinase (Trk) family of receptor tyrosine kinases (TrkA, TrkB and TrkC). In addition, each neurotrophin activates p75 neurotrophin receptor (p75NTR), a member of the tumour necrosis factor receptor superfamily. Through Trk receptors, neurotrophins activate Ras, phosphatidyl inositol-3 (PI3)-kinase, phospholipase C-gamma1 and signalling pathways controlled through these proteins, such as the MAP kinases. Activation of p75NTR results in activation of the nuclear factor-kappaB (NF-kappaB) and Jun kinase as well as other signalling pathways. Limiting quantities of neurotrophins during development control the number of surviving neurons to ensure a match between neurons and the requirement for a suitable density of target innervation. The neurotrophins also regulate cell fate decisions, axon growth, dendrite growth and pruning and the expression of proteins, such as ion channels, transmitter biosynthetic enzymes and neuropeptide transmitters that are essential for normal neuronal function. Continued presence of the neurotrophins is required in the adult nervous system, where they control synaptic function and plasticity, and sustain neuronal survival, morphology and differentiation. They also have additional, subtler roles outside the nervous system. In recent years, three rare human genetic disorders, which result in deleterious effects on sensory perception, cognition and a variety of behaviours, have been shown to be attributable to mutations in brain-derived neurotrophic factor and two of the Trk receptors.
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              Requisite role of angiopoietin-1, a ligand for the TIE2 receptor, during embryonic angiogenesis.

              Vascular endothelial growth factor (VEGF), which acts via members of a family of endothelial-specific receptor tyrosine kinases, is the only factor that has been shown definitively to play a role in the formation of the embryonic vasculature. Only one other family of receptor tyrosine kinases, comprising TIE1 and TIE2, is largely endothelial cell specific. We have recently cloned a ligand for TIE2, termed Angiopoietin-1. Here we show that mice engineered to lack Angiopoietin-1 display angiogenic deficits reminiscent of those previously seen in mice lacking TIE2, demonstrating that Angiopoietin-1 is a primary physiologic ligand for TIE2 and that it has critical in vivo angiogenic actions that are distinct from VEGF and that are not reflected in the classic in vitro assays used to characterize VEGF. Angiopoietin-1 seems to play a crucial role in mediating reciprocal interactions between the endothelium and surrounding matrix and mesenchyme.
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                Author and article information

                Journal
                J Exp Med
                J. Exp. Med
                jem
                The Journal of Experimental Medicine
                The Rockefeller University Press
                0022-1007
                1540-9538
                19 November 2012
                : 209
                : 12
                : 2291-2305
                Affiliations
                [1 ]Division of Hematology/Medical Oncology and [2 ]Division of Cardiovascular Pathophysiology, Department of Medicine , [3 ]Department of Biochemistry , [4 ]Department of Cell and Developmental Biology , and [5 ]Department of Pathology, Weill Cornell Medical College, New York, NY 10065
                [6 ]Department of Physiology and Pharmacology, Oregon Health and Science University, Portland, OR 97239
                [7 ]Developmental Biology Program, Sloan-Kettering Institute, New York, NY 10065
                [8 ]Department of Medical Biochemistry, University of Aarhus, Aarhus DK-8000, Denmark
                [9 ]Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 21702
                Author notes
                CORRESPONDENCE B.L. Hempstead: blhempst@ 123456med.cornell.edu

                C.-J. Siao and C.U. Lorentz contributed equally to this paper.

                Article
                20111749
                10.1084/jem.20111749
                3501352
                23091165
                © 2012 Siao et al.

                This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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