title: ProNGF, a cytokine induced after myocardial infarction in humans, targets pericytes to promote microvascular damage and activation.
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.
authors.affiliation: Division of Hematology/Medical Oncology, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Chia-Jen
authors.initials: CJ
authors.lastname: Siao
authors.forename: Christina U
authors.initials: CU
authors.lastname: Lorentz
authors.forename: Pouneh
authors.initials: P
authors.lastname: Kermani
authors.forename: Tina
authors.initials: T
authors.lastname: Marinic
authors.forename: John
authors.initials: J
authors.lastname: Carter
authors.forename: Kelly
authors.initials: K
authors.lastname: McGrath
authors.forename: Victoria A
authors.initials: VA
authors.lastname: Padow
authors.forename: Willie
authors.initials: W
authors.lastname: Mark
authors.forename: Domenick J
authors.initials: DJ
authors.lastname: Falcone
authors.forename: Leona
authors.initials: L
authors.lastname: Cohen-Gould
authors.forename: Diana C
authors.initials: DC
authors.lastname: Parrish
authors.forename: Beth A
authors.initials: BA
authors.lastname: Habecker
authors.forename: Anders
authors.initials: A
authors.lastname: Nykjaer
authors.forename: Lora H
authors.initials: LH
authors.lastname: Ellenson
authors.forename: Lino
authors.initials: L
authors.lastname: Tessarollo
authors.forename: Barbara L
authors.initials: BL
authors.lastname: Hempstead
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D004452:Echocardiography; D004797:Enzyme-Linked Immunosorbent Assay; D055879:Gene Knock-In Techniques; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008854:Microscopy, Electron; D008856:Microscopy, Fluorescence; D055806:Microvessels / Q000378:metabolism / Q000473:pathology*; D016297:Mutagenesis, Site-Directed; D009203:Myocardial Infarction / Q000378:metabolism* / Q000473:pathology; D020932:Nerve Growth Factor / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000378:metabolism; D020286:Pericytes / Q000378:metabolism*; D011498:Protein Precursors / Q000378:metabolism*; D017475:Receptors, Nerve Growth Factor / Q000172:deficiency / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism* / Q000473:pathology
chemical_list: D017931:DNA Primers; C484065:NGFR protein, human; D009419:Nerve Tissue Proteins; D011498:Protein Precursors; D017475:Receptors, Nerve Growth Factor; C061397:pro-nerve growth factor, human; D020932:Nerve Growth Factor