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

Chia Jen Siao, Christina U. Lorentz, Pouneh Kermani, Tina Marinic, John Carter, Kelly McGrath, Victoria A. Padow, Willie Mark, Domenick J. Falcone, Cohen Gould Leona, Diana C. Parrish, Beth Habecker, Anders Nykjaer, Lora H. Ellenson, Lino Tessarollo, Barbara L. Hempstead

Research output: Contribution to journalArticle

37 Citations (Scopus)

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 (p75NTR) and sortilin receptors to mediate proapoptotic responses. We describe induction of proNGF by cardiomyocytes, and p75NTR 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 p75NTR 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 p75NTR in proNGF-expressing mice rescues the phenotype, confirming the importance of p75NTR-expressing pericytes in the development of microvascular injury. Furthermore, deficiency in p75NTR 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.

Original languageEnglish (US)
Pages (from-to)2291-2305
Number of pages15
JournalJournal of Experimental Medicine
Volume209
Issue number12
DOIs
StatePublished - Nov 2012

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Nerve Growth Factor Receptor
Pericytes
Myocardial Infarction
Cytokines
Nerve Growth Factor
Cardiac Myocytes
Capillary Permeability
Arterioles
Reperfusion Injury
Cardiomyopathies
Brain Injuries
Coronary Vessels
Up-Regulation
Ischemia
Perfusion
Alleles
Pathology
Phenotype
Wounds and Injuries

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

Siao, C. J., Lorentz, C. U., Kermani, P., Marinic, T., Carter, J., McGrath, K., ... Hempstead, B. L. (2012). ProNGF, a cytokine induced after myocardial infarction in humans, targets pericytes to promote microvascular damage and activation. Journal of Experimental Medicine, 209(12), 2291-2305. https://doi.org/10.1084/jem.20111749

ProNGF, a cytokine induced after myocardial infarction in humans, targets pericytes to promote microvascular damage and activation. / Siao, Chia Jen; Lorentz, Christina U.; Kermani, Pouneh; Marinic, Tina; Carter, John; McGrath, Kelly; Padow, Victoria A.; Mark, Willie; Falcone, Domenick J.; Leona, Cohen Gould; Parrish, Diana C.; Habecker, Beth; Nykjaer, Anders; Ellenson, Lora H.; Tessarollo, Lino; Hempstead, Barbara L.

In: Journal of Experimental Medicine, Vol. 209, No. 12, 11.2012, p. 2291-2305.

Research output: Contribution to journalArticle

Siao, CJ, Lorentz, CU, Kermani, P, Marinic, T, Carter, J, McGrath, K, Padow, VA, Mark, W, Falcone, DJ, Leona, CG, Parrish, DC, Habecker, B, Nykjaer, A, Ellenson, LH, Tessarollo, L & Hempstead, BL 2012, 'ProNGF, a cytokine induced after myocardial infarction in humans, targets pericytes to promote microvascular damage and activation', Journal of Experimental Medicine, vol. 209, no. 12, pp. 2291-2305. https://doi.org/10.1084/jem.20111749
Siao, Chia Jen ; Lorentz, Christina U. ; Kermani, Pouneh ; Marinic, Tina ; Carter, John ; McGrath, Kelly ; Padow, Victoria A. ; Mark, Willie ; Falcone, Domenick J. ; Leona, Cohen Gould ; Parrish, Diana C. ; Habecker, Beth ; Nykjaer, Anders ; Ellenson, Lora H. ; Tessarollo, Lino ; Hempstead, Barbara L. / ProNGF, a cytokine induced after myocardial infarction in humans, targets pericytes to promote microvascular damage and activation. In: Journal of Experimental Medicine. 2012 ; Vol. 209, No. 12. pp. 2291-2305.
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AU - Lorentz, Christina U.

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AU - Carter, John

AU - McGrath, Kelly

AU - Padow, Victoria A.

AU - Mark, Willie

AU - Falcone, Domenick J.

AU - Leona, Cohen Gould

AU - Parrish, Diana C.

AU - Habecker, Beth

AU - Nykjaer, Anders

AU - Ellenson, Lora H.

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