Chia-Jen Siao 1 , Christina U. Lorentz 1 , Pouneh Kermani 1 , Tina Marinic 1 , John Carter 2 , Kelly McGrath 1 , Victoria A. Padow 1 , Willie Mark 7 , Domenick J. Falcone 5 , Leona Cohen-Gould 3 , 4 , Diana C. Parrish 6 , Beth A. Habecker 6 , Anders Nykjaer 8 , Lora H. Ellenson 5 , Lino Tessarollo 9 , Barbara L. Hempstead , 1
19 November 2012
proNGF and p75NTR are induced following fatal myocardial infraction and are required for the development of microvascular injury.
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.