TBX20 Regulates Angiogenesis Through the Prokineticin 2-Prokineticin Receptor 1 Pathway

Research output: Contribution to journalArticle

Shu Meng, Qilin Gu, Xiaojie Yang, Jie Lv, Iris Owusu, Gianfranco Matrone, Kaifu Chen, John P. Cooke, Longhou Fang

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 (prokineticin 2) 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 intraplug angiogenesis. Furthermore, recombinant PROK2 administration enhanced angiogenesis and blood flow recovery in murine hind-limb ischemia. In zebrafish, transient knockdown of tbx20 by morpholino antisense oligos or genetic disruption of tbx20 by CRISPR/Cas9 impaired angiogenesis. Furthermore, loss of prok2 or 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 (prokineticin receptor 1) 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 proangiogenic effect of vascular endothelial growth factor. This pathway may be a therapeutic target in the treatment of diseases with dysregulated angiogenesis.

Original languageEnglish (US)
Pages (from-to)913-928
Number of pages16
JournalCirculation
Volume138
Issue number9
DOIs
StatePublished - Aug 28 2018

PMID: 29545372

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TBX20 Regulates Angiogenesis Through the Prokineticin 2-Prokineticin Receptor 1 Pathway. / Meng, Shu; Gu, Qilin; Yang, Xiaojie; Lv, Jie; Owusu, Iris; Matrone, Gianfranco; Chen, Kaifu; Cooke, John P.; Fang, Longhou.

In: Circulation, Vol. 138, No. 9, 28.08.2018, p. 913-928.

Research output: Contribution to journalArticle

Harvard

Meng, S, Gu, Q, Yang, X, Lv, J, Owusu, I, Matrone, G, Chen, K, Cooke, JP & Fang, L 2018, 'TBX20 Regulates Angiogenesis Through the Prokineticin 2-Prokineticin Receptor 1 Pathway' Circulation, vol. 138, no. 9, pp. 913-928. https://doi.org/10.1161/CIRCULATIONAHA.118.033939

APA

Meng, S., Gu, Q., Yang, X., Lv, J., Owusu, I., Matrone, G., ... Fang, L. (2018). TBX20 Regulates Angiogenesis Through the Prokineticin 2-Prokineticin Receptor 1 Pathway. Circulation, 138(9), 913-928. https://doi.org/10.1161/CIRCULATIONAHA.118.033939

Vancouver

Meng S, Gu Q, Yang X, Lv J, Owusu I, Matrone G et al. TBX20 Regulates Angiogenesis Through the Prokineticin 2-Prokineticin Receptor 1 Pathway. Circulation. 2018 Aug 28;138(9):913-928. https://doi.org/10.1161/CIRCULATIONAHA.118.033939

Author

Meng, Shu ; Gu, Qilin ; Yang, Xiaojie ; Lv, Jie ; Owusu, Iris ; Matrone, Gianfranco ; Chen, Kaifu ; Cooke, John P. ; Fang, Longhou. / TBX20 Regulates Angiogenesis Through the Prokineticin 2-Prokineticin Receptor 1 Pathway. In: Circulation. 2018 ; Vol. 138, No. 9. pp. 913-928.

BibTeX

@article{5f747ca4d13a42f0b4b746f3ae79ee10,
title = "TBX20 Regulates Angiogenesis Through the Prokineticin 2-Prokineticin Receptor 1 Pathway",
abstract = "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 (prokineticin 2) 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 intraplug angiogenesis. Furthermore, recombinant PROK2 administration enhanced angiogenesis and blood flow recovery in murine hind-limb ischemia. In zebrafish, transient knockdown of tbx20 by morpholino antisense oligos or genetic disruption of tbx20 by CRISPR/Cas9 impaired angiogenesis. Furthermore, loss of prok2 or 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 (prokineticin receptor 1) 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 proangiogenic effect of vascular endothelial growth factor. This pathway may be a therapeutic target in the treatment of diseases with dysregulated angiogenesis.",
keywords = "G-protein-coupled, neovascularization, physiologic, peripheral arterial disease, receptors",
author = "Shu Meng and Qilin Gu and Xiaojie Yang and Jie Lv and Iris Owusu and Gianfranco Matrone and Kaifu Chen and Cooke, {John P.} and Longhou Fang",
year = "2018",
month = "8",
day = "28",
doi = "10.1161/CIRCULATIONAHA.118.033939",
language = "English (US)",
volume = "138",
pages = "913--928",
journal = "Circulation",
issn = "0009-7322",
publisher = "Lippincott Williams and Wilkins",
number = "9",

}

RIS

TY - JOUR

T1 - TBX20 Regulates Angiogenesis Through the Prokineticin 2-Prokineticin Receptor 1 Pathway

AU - Meng, Shu

AU - Gu, Qilin

AU - Yang, Xiaojie

AU - Lv, Jie

AU - Owusu, Iris

AU - Matrone, Gianfranco

AU - Chen, Kaifu

AU - Cooke, John P.

AU - Fang, Longhou

PY - 2018/8/28

Y1 - 2018/8/28

N2 - 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 (prokineticin 2) 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 intraplug angiogenesis. Furthermore, recombinant PROK2 administration enhanced angiogenesis and blood flow recovery in murine hind-limb ischemia. In zebrafish, transient knockdown of tbx20 by morpholino antisense oligos or genetic disruption of tbx20 by CRISPR/Cas9 impaired angiogenesis. Furthermore, loss of prok2 or 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 (prokineticin receptor 1) 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 proangiogenic effect of vascular endothelial growth factor. This pathway may be a therapeutic target in the treatment of diseases with dysregulated angiogenesis.

AB - 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 (prokineticin 2) 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 intraplug angiogenesis. Furthermore, recombinant PROK2 administration enhanced angiogenesis and blood flow recovery in murine hind-limb ischemia. In zebrafish, transient knockdown of tbx20 by morpholino antisense oligos or genetic disruption of tbx20 by CRISPR/Cas9 impaired angiogenesis. Furthermore, loss of prok2 or 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 (prokineticin receptor 1) 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 proangiogenic effect of vascular endothelial growth factor. This pathway may be a therapeutic target in the treatment of diseases with dysregulated angiogenesis.

KW - G-protein-coupled

KW - neovascularization, physiologic

KW - peripheral arterial disease

KW - receptors

UR - http://www.scopus.com/inward/record.url?scp=85055602385&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85055602385&partnerID=8YFLogxK

U2 - 10.1161/CIRCULATIONAHA.118.033939

DO - 10.1161/CIRCULATIONAHA.118.033939

M3 - Article

VL - 138

SP - 913

EP - 928

JO - Circulation

T2 - Circulation

JF - Circulation

SN - 0009-7322

IS - 9

ER -

ID: 42036158