TBX20 Regulates Angiogenesis Through the PROK2-PROKR1 Pathway

Meng, S., Gu, Q., Yang, X., Lv, J., Owusu, I., Matrone, G., Chen, K., Cooke, J.P., Fang, L.
Circulation   138(9): 913-928 (Journal)
Registered Authors
Fang, Longhou, Gu, Qilin
G protein coupled receptor, PAD, Proangiogenic capacitor, TBX20-PROK2-PROKR1 signaling axis, angiogenesis
MeSH Terms
  • Angiogenesis Inducing Agents/pharmacology
  • Animals
  • Animals, Genetically Modified
  • Disease Models, Animal
  • Gastrointestinal Hormones/genetics
  • Gastrointestinal Hormones/metabolism*
  • Gene Expression Regulation, Developmental
  • Hindlimb
  • Human Umbilical Vein Endothelial Cells/metabolism
  • Humans
  • Ischemia/drug therapy
  • Ischemia/genetics
  • Ischemia/metabolism*
  • Ischemia/physiopathology
  • Male
  • Mice, Inbred NOD
  • Mice, SCID
  • Muscle, Skeletal/blood supply*
  • Neovascularization, Physiologic*/drug effects
  • Neuropeptides/genetics
  • Neuropeptides/metabolism*
  • Recombinant Proteins/pharmacology
  • Signal Transduction
  • T-Box Domain Proteins/genetics
  • T-Box Domain Proteins/metabolism*
  • Zebrafish
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
29545372 Full text @ Circulation
Background -Angiogenesis is integral for embryogenesis, and targeting angiogenesis improves the outcome of many pathological conditions in patients. TBX20 is a crucial transcription factor for embryonic development, and its deficiency is associated with congenital heart disease. However, the role of TBX20 in angiogenesis has not been described.
Methods-Loss- and gain-of-function approaches were used to explore the role of TBX20 in angiogenesis both in vitro and in vivo Angiogenesis gene array was used to identify key downstream targets of TBX20.
Results-Unbiased gene array survey showed that TBX20 knockdown profoundly reduced angiogenesis-associated PROK2 gene expression. Indeed, loss of TBX20 hindered endothelial cell migration and in vitro angiogenesis. In a murine angiogenesis model using subcutaneously implanted matrigel plugs, we observed that TBX20 deficiency markedly reduced PROK2 expression and restricted intra-plug angiogenesis. Furthermore, recombinant PROK2 administration enhanced angiogenesis and blood flow recovery in murine hindlimb ischemia. In zebrafish, transient knockdown of tbx20 by morpholino antisense oligos (MO) or genetic disruption of tbx20 by CRISPR/Cas9 impaired angiogenesis. Furthermore, loss of prok2or its cognate receptor prokr1a also limited angiogenesis. In contrast, overexpression of prok2 or prokr1a rescued the impaired angiogenesis in tbx20 deficient animals.
Conclusions-Our study identifies TBX20 as a novel transcription factor regulating angiogenesis through the PROK2-PROKR1 pathway in both development and disease, and reveals a novel mode of angiogenic regulation whereby the TBX20-PROK2-PROKR1 signaling cascade may act as a "biological capacitor" to relay and sustain the pro-angiogenic effect of VEGF. This pathway may be a therapeutic target in the treatment of diseases with dysregulated angiogenesis.
Genes / Markers
Show all Figures
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Engineered Foreign Genes
Errata and Notes