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

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

doi:10.1083/jcb1993oia3

Cited by 11 publications

(19 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Studies performed with a mouse model of cardiac ischemia-reperfusion injury have demonstrated that microvascular pericytes are responsible for the occurrence of endothelial dysfunction with a mechanism involving the neurotrophine receptor p75 NTR [73]. This mechanism would work also in human subjects.…”

Section: Ischemia/reperfusion Injurymentioning

confidence: 99%

“…This mechanism would work also in human subjects. During ischemia, cardiomyocytes rapidly increase the secretion of pro-Nerve Growth Factor, which binds to the p75 NTR on the surface of PDGFR- pos pericytes and this results in a modification of pericytes architecture including a reduction of vascular coverage and a shortening of cell processes, finally disrupting the endothelial cell-pericyte interaction and provoking an increase of vascular permeability; the cardiomyopathy becomes lethal in adult mice [73]. Another phenomenon involving pericytes occurring in ischemic patients is the coronary noreflow, described as the failure to achieve adequate reperfusion of the cardiac microcirculation after the reperfusion that follows a coronary artery obstruction.…”

Section: Ischemia/reperfusion Injurymentioning

confidence: 99%

See 1 more Smart Citation

Discovering cardiac pericyte biology: From physiopathological mechanisms to potential therapeutic applications in ischemic heart disease

Avolio

Madeddu

2016

Vascular Pharmacology

View full text Add to dashboard Cite

Microvascular pericytes and the more recently discovered adventitial pericyte-like progenitor cells are a subpopulation of vascular stem cells closely associated with small and large blood vessels respectively. These populations of perivascular cells are remarkably abundant in the heart. Pericytes control important physiological processes such as angiogenesis, blood flow and vascular permeability. In the heart, this pleiotropic activity makes pericytes extremely interesting for applications in regenerative medicine. On the other hand, dysfunction of pericytes could participate in the pathogenesis of cardiovascular disease, such as arterial hypertension, fibro-calcific cardiovascular remodeling, myocardial edema and post-ischemic coronary no-reflow. On a therapeutic standpoint, preclinical studies in small animal models of myocardial infarction have demonstrated the healing potential of pericytes transplantation, which has been ascribed to direct vascular incorporation and paracrine pro-angiogenic and anti-apoptotic activities. These promising findings open the door to the clinical use of pericytes for the treatment of cardiovascular diseases.

show abstract

Section: Ischemia/reperfusion Injurymentioning

confidence: 99%

Section: Ischemia/reperfusion Injurymentioning

confidence: 99%

Discovering cardiac pericyte biology: From physiopathological mechanisms to potential therapeutic applications in ischemic heart disease

Avolio

Madeddu

2016

Vascular Pharmacology

View full text Add to dashboard Cite

show abstract

“…Wild‐type C57BL/6J and p75 NTR knockout mice (B6.129S4‐ Ngfr tm1Jae /J) were obtained from the Jackson Laboratory (Bar Harbor, Maine). The B6.129S4‐Ngfr tm1Jae /J mice, which contain two mutated exon III alleles preventing the expression of functional p75 NTR (Siao et al, ), were backcrossed to the C57BL/6J background. The p75 NTR−/− mice were genotyped upon arrival at Oregon Health and Science University (Portland, OR) to confirm the presence of the p75 NTR−/− mutation and a C57BL/6J genetic background, and a colony was maintained using homozygous breeder pairs, with additional genotyping every 6 months.…”

Section: Methodsmentioning

confidence: 99%

BMP7‐induced dendritic growth in sympathetic neurons requires p75^NTR signaling

Courter

Shaffo

Ghogha

et al. 2016

Developmental Neurobiology

Self Cite

View full text Add to dashboard Cite

Dendritic morphology is a critical determinant of neuronal connectivity, and in postganglionic sympathetic neurons, tonic activity correlates directly with the size of the dendritic arbor. Thus, identifying signaling mechanisms that regulate dendritic arborization of sympathetic neurons is important to understanding how functional neural circuitry is established and maintained in the sympathetic nervous system. Bone morphogenetic proteins (BMPs) promote dendritic growth in sympathetic neurons; however, downstream signaling events that link BMP receptor activation to dendritic growth are poorly characterized. We previously reported that BMP7 upregulates p75NTR mRNA in cultured sympathetic neurons. This receptor is implicated in controlling dendritic growth in central neurons but whether p75NTR regulates dendritic growth in peripheral neurons is not known. Here, we demonstrate that BMP7 increases p75NTR protein in cultured sympathetic neurons, and this effect is blocked by pharmacologic inhibition of signaling via BMPR1. BMP7 does not trigger dendritic growth in sympathetic neurons dissociated from superior cervical ganglia (SCG) of p75NTR nullizygous mice, and overexpression of p75NTR in p75NTR−/− neurons is sufficient to cause dendritic growth even in the absence of BMP7. Morphometric analyses of SCG from wildtype versus p75NTR nullizygous mice at 3, 6 and 12–16 weeks of age indicated that genetic deletion of p75NTR does not prevent dendritic growth but does stunt dendritic maturation in sympathetic neurons. These data support the hypotheses that p75NTR is involved in downstream signaling events that mediate BMP7-induced dendritic growth in sympathetic neurons, and suggest that p75NTR signaling positively modulates dendritic complexity in sympathetic neurons in vivo.

show abstract

“…A cleavage‐resistant proNGF knock‐in mouse exhibits cardiac microvascular endothelial activation, a decrease in pericyte process length, and increased vascular permeability, leading to lethal cardiomyopathy in adulthood (Siao et al . ). Genetic approaches were conducted by Yang and collaborators and by Siao and collaborators to confirm that the observed phenotypes of the cleavage‐resistant proBDNF and proNGF mouse lines were a gain of function of the precursors and not a consequence of the expected decrease in the mature forms (Siao et al .…”

Section: Prodomains As Part Of Active Pro‐protein Precursorsmentioning

confidence: 97%

“…Genetic approaches were conducted by Yang and collaborators and by Siao and collaborators to confirm that the observed phenotypes of the cleavage‐resistant proBDNF and proNGF mouse lines were a gain of function of the precursors and not a consequence of the expected decrease in the mature forms (Siao et al . ; Yang et al . ).…”

Section: Prodomains As Part Of Active Pro‐protein Precursorsmentioning

confidence: 99%

Growth factors and hormones pro‐peptides: the unexpected adventures of the BDNF prodomain

Zanin

Unsain

Anastasía

2017

Journal of Neurochemistry

View full text Add to dashboard Cite

Most growth factors and hormones are synthesized as prepro-proteins which are processed to the biologically active mature protein. The pre-and prodomains are cleaved from the precursor protein in the secretory pathway or, in some cases, extracellularly. The canonical functions of these prodomains are to assist in folding and stabilization of the mature domain, to direct intra and extracellular localization, to facilitate storage, and to regulate bioavailability of their mature counterpart. Recently, exciting evidence has revealed that prodomains of certain growth factors, after cleaved from the precursor pro-protein, can act as independent active signaling molecules. In this review, we discuss the various classical functions of prodomains, and the biological consequences of these pro-peptides acting as ligands. We will focus our attention on the brain-derived neurotrophic factor prodomain (pBDNF), which has been recently described as a novel secreted ligand influencing neuronal morphology and physiology. Keywords: active prodomains, biosynthetic pathway, pBDNF, precursor cleavage peptides, proBDNF, Val66Met polymorphism. Most growth factors and hormones are synthetized as prepro-proteins. These prefixes are used to describe the intermediate processed forms of a protein before it is active and at the appropriate location. The prefix 'pre' indicates the presence of an N-terminal sequence that targets the precursor pro-protein to the secretory pathway or an intracellular compartment. For this reason, this sequence is referred to as 'signal peptide' or 'signal sequence'. Signal peptides, which are typically from 5 to 50 residues, are cleaved by signal peptidases and quickly degraded. Later, it was discovered that many proteins require additional proteolytic processing to become functional. This additional step involves cleavage of a subsequent N-terminal peptide, which is indicated by the prefix 'pro' accounting for prodomain (or pro-peptide; example in Fig. 1a). The processing of pro-proteins to remove their prodomains requires enzymes including proprotein convertases (or proconvertases), which are present in the Golgi apparatus or in secretory vesicles, or extracellular enzymes such as matrix metalloproteinases among others. For example, the pro-protein of the neurotrophin brainderived neurotrophic factor (proBDNF), can be cleaved by furin and other proconvertases in the trans-Golgi network or Received December 29, 2016; revised manuscript received February 8, 2017; accepted February 13, 2017. Address correspondence and reprint requests to Agustin Anastasia, Instituto de Investigaci on M edica Mercedes y Martin Ferreyra, (INIMEC-CONICET-Universidad Nacional de C ordoba), Friuli 2434, C ordoba, C ordoba 5016, Argentina. E-mail: aanastasia@immf.uncor.edu.Abbreviations used: AMPA, a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; BMP, bone morphogenetic protein; CD, circular dichroism; DNSP, dopamine neuron-stimulating peptide; GDNF, glial cell line-derived neurotrophic factor; GPR146, G-prote...

show abstract

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

Cited by 11 publications

References 37 publications

Discovering cardiac pericyte biology: From physiopathological mechanisms to potential therapeutic applications in ischemic heart disease

Discovering cardiac pericyte biology: From physiopathological mechanisms to potential therapeutic applications in ischemic heart disease

BMP7‐induced dendritic growth in sympathetic neurons requires p75^NTR signaling

Growth factors and hormones pro‐peptides: the unexpected adventures of the BDNF prodomain

Contact Info

Product

Resources

About

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

Cited by 11 publications

References 37 publications

Discovering cardiac pericyte biology: From physiopathological mechanisms to potential therapeutic applications in ischemic heart disease

Discovering cardiac pericyte biology: From physiopathological mechanisms to potential therapeutic applications in ischemic heart disease

BMP7‐induced dendritic growth in sympathetic neurons requires p75NTR signaling

Growth factors and hormones pro‐peptides: the unexpected adventures of the BDNF prodomain

Contact Info

Product

Resources

About

BMP7‐induced dendritic growth in sympathetic neurons requires p75^NTR signaling