Trkb signaling in pericytes is required for cardiac microvessel stabilization

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

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Article numbere87406
JournalPLoS One
Volume9
Issue number1
DOIs
StatePublished - Jan 31 2014

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Pericytes
neurotrophins
Microvessels
blood vessels
Brain-Derived Neurotrophic Factor
Stabilization
brain
Endothelial cells
endothelial cells
myosin light chains
Blood Vessels
Myosin Light Chains
Phosphorylation
Endothelial Cells
smooth muscle
myocytes
Blood vessels
phosphorylation
embryo (animal)
Smooth Muscle Myocytes

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Anastasia, A., Deinhardt, K., Wang, S., Martin, L., Nichol, D., Irmady, K., ... Kermani, P. (2014). Trkb signaling in pericytes is required for cardiac microvessel stabilization. PLoS One, 9(1), [e87406]. https://doi.org/10.1371/journal.pone.0087406

Trkb signaling in pericytes is required for cardiac microvessel stabilization. / Anastasia, Agustin; Deinhardt, Katrin; Wang, Shiyang; Martin, Laura; Nichol, Donna; Irmady, Krithi; Trinh, Jasmine; Parada, Luis; Rafii, Shahin; Hempstead, Barbara L.; Kermani, Pouneh.

In: PLoS One, Vol. 9, No. 1, e87406, 31.01.2014.

Research output: Contribution to journalArticle

Anastasia, A, Deinhardt, K, Wang, S, Martin, L, Nichol, D, Irmady, K, Trinh, J, Parada, L, Rafii, S, Hempstead, BL & Kermani, P 2014, 'Trkb signaling in pericytes is required for cardiac microvessel stabilization', PLoS One, vol. 9, no. 1, e87406. https://doi.org/10.1371/journal.pone.0087406
Anastasia A, Deinhardt K, Wang S, Martin L, Nichol D, Irmady K et al. Trkb signaling in pericytes is required for cardiac microvessel stabilization. PLoS One. 2014 Jan 31;9(1). e87406. https://doi.org/10.1371/journal.pone.0087406
Anastasia, Agustin ; Deinhardt, Katrin ; Wang, Shiyang ; Martin, Laura ; Nichol, Donna ; Irmady, Krithi ; Trinh, Jasmine ; Parada, Luis ; Rafii, Shahin ; Hempstead, Barbara L. ; Kermani, Pouneh. / Trkb signaling in pericytes is required for cardiac microvessel stabilization. In: PLoS One. 2014 ; Vol. 9, No. 1.
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