The University of Southampton
University of Southampton Institutional Repository

Trkb signaling in pericytes is required for cardiac microvessel stabilization

Trkb signaling in pericytes is required for cardiac microvessel stabilization
Trkb signaling in pericytes is required for cardiac microvessel stabilization
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.
1932-6203
e87406
Anastasia, Agustin
ed578679-72dc-4b72-b520-86f74a413e7a
Deinhardt, Katrin
5f4fe23b-2317-499f-ba6d-e639a4885dc1
Wang, Shiyang
ba544c05-80d9-49ca-9fac-46599db47f7b
Martin, Laura
ce923f96-bcd5-4181-b3d0-054b4e0b5d3f
Nichol, Donna
57495ee9-bdd2-4ed3-b0c9-f365a06c1485
Irmady, Krithi
a3267628-c7ba-4ee3-a958-70a3e203245c
Trinh, Jasmine
023a2931-7fd4-4bd1-a423-20d7a11e1714
Parada, Luis
18ce75e6-e261-4ae4-8d54-4c9decd5f342
Rafii, Shahin
65163d0e-dd37-44bd-a852-3c19d58da7d7
Hempstead, Barbara L.
2dcb38a7-30cd-4ad2-948c-b651865275b0
Kermani, Pouneh
71fc18f7-6abd-4963-beb2-1bd6ee3f2d3a
Anastasia, Agustin
ed578679-72dc-4b72-b520-86f74a413e7a
Deinhardt, Katrin
5f4fe23b-2317-499f-ba6d-e639a4885dc1
Wang, Shiyang
ba544c05-80d9-49ca-9fac-46599db47f7b
Martin, Laura
ce923f96-bcd5-4181-b3d0-054b4e0b5d3f
Nichol, Donna
57495ee9-bdd2-4ed3-b0c9-f365a06c1485
Irmady, Krithi
a3267628-c7ba-4ee3-a958-70a3e203245c
Trinh, Jasmine
023a2931-7fd4-4bd1-a423-20d7a11e1714
Parada, Luis
18ce75e6-e261-4ae4-8d54-4c9decd5f342
Rafii, Shahin
65163d0e-dd37-44bd-a852-3c19d58da7d7
Hempstead, Barbara L.
2dcb38a7-30cd-4ad2-948c-b651865275b0
Kermani, Pouneh
71fc18f7-6abd-4963-beb2-1bd6ee3f2d3a

Anastasia, Agustin, Deinhardt, Katrin, Wang, Shiyang, Martin, Laura, Nichol, Donna, Irmady, Krithi, Trinh, Jasmine, Parada, Luis, Rafii, Shahin, Hempstead, Barbara L. and Kermani, Pouneh (2014) Trkb signaling in pericytes is required for cardiac microvessel stabilization. PLoS ONE, 9 (1), e87406. (doi:10.1371/journal.pone.0087406). (PMID:24498100)

Record type: Article

Abstract

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.

Other
fetchObject.action_uri=info_doi%2F10.1371%2Fjournal.pone.0087406&representation=PDF - Version of Record
Available under License Creative Commons Attribution.
Download (12MB)

More information

Accepted/In Press date: 23 December 2013
e-pub ahead of print date: 31 January 2014
Published date: 31 January 2014
Organisations: Centre for Biological Sciences

Identifiers

Local EPrints ID: 362631
URI: http://eprints.soton.ac.uk/id/eprint/362631
ISSN: 1932-6203
PURE UUID: 2f139c46-aa7d-49f8-8374-2cea3179b140
ORCID for Katrin Deinhardt: ORCID iD orcid.org/0000-0002-6473-5298

Catalogue record

Date deposited: 03 Mar 2014 11:55
Last modified: 26 Nov 2019 01:36

Export record

Altmetrics

Contributors

Author: Agustin Anastasia
Author: Shiyang Wang
Author: Laura Martin
Author: Donna Nichol
Author: Krithi Irmady
Author: Jasmine Trinh
Author: Luis Parada
Author: Shahin Rafii
Author: Barbara L. Hempstead
Author: Pouneh Kermani

University divisions

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×