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.
Department of Medicine of Weill Cornell Medical College, New York, New York, United States of America.
Agustin
A
Anastasia
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.
Katrin
K
Deinhardt
Department of Medicine of Weill Cornell Medical College, New York, New York, United States of America.
Shiyang
S
Wang
Department of Medicine of Weill Cornell Medical College, New York, New York, United States of America.
Laura
L
Martin
Cell and Developmental Biology of Weill Cornell Medical College, New York, New York, United States of America.
Donna
D
Nichol
Department of Medicine of Weill Cornell Medical College, New York, New York, United States of America.
Krithi
K
Irmady
Department of Medicine of Weill Cornell Medical College, New York, New York, United States of America.
Jasmine
J
Trinh
Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
Luis
L
Parada
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.
Shahin
S
Rafii
Department of Medicine of Weill Cornell Medical College, New York, New York, United States of America.
Barbara L
BL
Hempstead
Cell and Developmental Biology of Weill Cornell Medical College, New York, New York, United States of America.
Pouneh
P
Kermani
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D002199:Capillary Permeability / Q000502:physiology; D003331:Coronary Vessels / Q000166:cytology / Q000196:embryology / Q000201:enzymology*; D006330:Heart Defects, Congenital / Q000196:embryology / Q000201:enzymology / Q000235:genetics; D006801:Humans; D008562:Membrane Glycoproteins; D051379:Mice; D008817:Mice, Mutant Strains; D009206:Myocardium / Q000201:enzymology*; D032389:Myocytes, Smooth Muscle / Q000201:enzymology*; D020286:Pericytes / Q000166:cytology / Q000201:enzymology*; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases; D020813:Receptor, trkB; D015398:Signal Transduction / Q000502:physiology*; D054460:rho-Associated Kinases / Q000235:genetics / Q000378:metabolism
D019208:Brain-Derived Neurotrophic Factor; D008562:Membrane Glycoproteins; C579455:BDNF protein, human; D011494:Protein Kinases; D011505:Protein-Tyrosine Kinases; D020813:Receptor, trkB; C000591259:tropomyosin-related kinase-B, human; D054460:rho-Associated Kinases