PMID- 24498100
OWN - NLM
STAT- MEDLINE
DCOM- 20141015
LR  - 20211021
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 9
IP  - 1
DP  - 2014
TI  - Trkb signaling in pericytes is required for cardiac microvessel stabilization.
PG  - e87406
LID - 10.1371/journal.pone.0087406 [doi]
LID - e87406
AB  - Pericyte and vascular smooth muscle cell (SMC) recruitment to the developing 
      vasculature is an important step in blood vessel maturation. Brain-derived 
      neurotrophic factor (BDNF), expressed by endothelial cells, activates the 
      receptor tyrosine kinase TrkB to stabilize the cardiac microvasculature in the 
      perinatal period. However, the effects of the BDNF/TrkB signaling on 
      pericytes/SMCs and the mechanisms downstream of TrkB that promote vessel 
      maturation are unknown. To confirm the involvement of TrkB in vessel maturation, 
      we evaluated TrkB deficient (trkb (-/-)) embryos and observed severe cardiac 
      vascular abnormalities leading to lethality in late gestation to early prenatal 
      life. Ultrastructural analysis demonstrates that trkb(-/-) embryos exhibit 
      defects in endothelial cell integrity and perivascular edema. As TrkB is 
      selectively expressed by pericytes and SMCs in the developing cardiac 
      vasculature, we generated mice deficient in TrkB in these cells. Mice with TrkB 
      deficiency in perivascular cells exhibit reduced pericyte/SMC coverage of the 
      cardiac microvasculature, abnormal endothelial cell ultrastructure, and increased 
      vascular permeability. To dissect biological actions and the signaling pathways 
      downstream of TrkB in pericytes/SMCs, human umbilical SMCs were treated with 
      BDNF. This induced membranous protrusions and cell migration, events dependent on 
      myosin light chain phosphorylation. Moreover, inhibition of Rho GTPase and the 
      Rho-associated protein kinase (ROCK) prevented membrane protrusion and myosin 
      light chain phosphorylation in response to BDNF. These results suggest an 
      important role for BDNF in regulating migration of TrkB-expressing pericytes/SMCs 
      to promote cardiac blood vessel ensheathment and functional integrity during 
      development.
FAU - Anastasia, Agustin
AU  - Anastasia A
AD  - Department of Medicine of Weill Cornell Medical College, New York, New York, 
      United States of America.
FAU - Deinhardt, Katrin
AU  - Deinhardt K
AD  - Department of Molecular Neurobiology, Skirball Institute, New York, New York, 
      United States of America ; Centre for Biological Sciences and Institute for Life 
      Sciences, University of Southampton, Southampton, United Kingdom.
FAU - Wang, Shiyang
AU  - Wang S
AD  - Department of Medicine of Weill Cornell Medical College, New York, New York, 
      United States of America.
FAU - Martin, Laura
AU  - Martin L
AD  - Department of Medicine of Weill Cornell Medical College, New York, New York, 
      United States of America.
FAU - Nichol, Donna
AU  - Nichol D
AD  - Cell and Developmental Biology of Weill Cornell Medical College, New York, New 
      York, United States of America.
FAU - Irmady, Krithi
AU  - Irmady K
AD  - Department of Medicine of Weill Cornell Medical College, New York, New York, 
      United States of America.
FAU - Trinh, Jasmine
AU  - Trinh J
AD  - Department of Medicine of Weill Cornell Medical College, New York, New York, 
      United States of America.
FAU - Parada, Luis
AU  - Parada L
AD  - Department of Developmental Biology, University of Texas Southwestern Medical 
      Center, Dallas, Texas, United States of America.
FAU - Rafii, Shahin
AU  - Rafii S
AD  - Howard Hughes Medical Institute, Ansary Stem Cell Institute, and Department of 
      Genetic Medicine, Weill Cornell Medical College, New York, New York, United 
      States of America.
FAU - Hempstead, Barbara L
AU  - Hempstead BL
AD  - Department of Medicine of Weill Cornell Medical College, New York, New York, 
      United States of America.
FAU - Kermani, Pouneh
AU  - Kermani P
AD  - Cell and Developmental Biology of Weill Cornell Medical College, New York, New 
      York, United States of America.
LA  - eng
GR  - P01 HL046403/HL/NHLBI NIH HHS/United States
GR  - P01 HL46403/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20140131
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Membrane Glycoproteins)
RN  - 7171WSG8A2 (BDNF protein, human)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.10.1 (Protein-Tyrosine Kinases)
RN  - EC 2.7.10.1 (Receptor, trkB)
RN  - EC 2.7.10.1 (tropomyosin-related kinase-B, human)
RN  - EC 2.7.11.1 (rho-Associated Kinases)
SB  - IM
MH  - Animals
MH  - Brain-Derived Neurotrophic Factor/genetics/metabolism
MH  - Capillary Permeability/physiology
MH  - Coronary Vessels/cytology/embryology/*enzymology
MH  - Heart Defects, Congenital/embryology/enzymology/genetics
MH  - Humans
MH  - Membrane Glycoproteins
MH  - Mice
MH  - Mice, Mutant Strains
MH  - Myocardium/*enzymology
MH  - Myocytes, Smooth Muscle/*enzymology
MH  - Pericytes/cytology/*enzymology
MH  - Protein Kinases/genetics/*metabolism
MH  - Protein-Tyrosine Kinases
MH  - Receptor, trkB
MH  - Signal Transduction/*physiology
MH  - rho-Associated Kinases/genetics/metabolism
PMC - PMC3909185
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2014/02/06 06:00
MHDA- 2014/10/16 06:00
PMCR- 2014/01/31
CRDT- 2014/02/06 06:00
PHST- 2013/06/24 00:00 [received]
PHST- 2013/12/24 00:00 [accepted]
PHST- 2014/02/06 06:00 [entrez]
PHST- 2014/02/06 06:00 [pubmed]
PHST- 2014/10/16 06:00 [medline]
PHST- 2014/01/31 00:00 [pmc-release]
AID - PONE-D-13-26116 [pii]
AID - 10.1371/journal.pone.0087406 [doi]
PST - epublish
SO  - PLoS One. 2014 Jan 31;9(1):e87406. doi: 10.1371/journal.pone.0087406. eCollection 
      2014.