ProNGF, a cytokine induced after myocardial infarction in humans, targets pericytes to promote microvascular damage and activation. Academic Article uri icon

Overview

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.

publication date

  • October 22, 2012

Research

keywords

  • Brain
  • Microvessels
  • Myocardial Infarction
  • Nerve Growth Factor
  • Pericytes
  • Protein Precursors
  • Reperfusion Injury

Identity

PubMed Central ID

  • PMC3501352

Scopus Document Identifier

  • 84871854423

Digital Object Identifier (DOI)

  • 10.1017/S1740925X09000015

PubMed ID

  • 23091165

Additional Document Info

volume

  • 209

issue

  • 12