Tumor necrosis factor-α receptor p75 is required in ischemia-induced neovascularization

David A. Goukassian; Gangjian Qin; Christine Dolan; Toshinori Murayama; Marcy Silver; Cynthia Curry; Elizabeth Eaton; Corinne Luedemann; Hong Ma; Takayuki Asahara; Victor Zak; Shanu Mehta; Aaron Burg; Tina Thorne; Raj Kishore; Douglas W. Losordo

doi:10.1161/CIRCULATIONAHA.106.647255

Tumor necrosis factor-α receptor p75 is required in ischemia-induced neovascularization

David A. Goukassian^*, Gangjian Qin, Christine Dolan, Toshinori Murayama, Marcy Silver, Cynthia Curry, Elizabeth Eaton, Corinne Luedemann, Hong Ma, Takayuki Asahara, Victor Zak, Shanu Mehta, Aaron Burg, Tina Thorne, Raj Kishore, Douglas W. Losordo

^*Corresponding author for this work

Medicine, Cardiology Division

Research output: Contribution to journal › Article › peer-review

84 Scopus citations

Abstract

BACKGROUND - Aging is a risk factor for coronary and peripheral artery disease. Tumor necrosis factor-α (TNF-α), a proinflammatory cytokine, is expressed in ischemic tissue and is known to modulate angiogenesis. Little is known about the role of TNF-α receptors (TNFR1/p55 and TNFR2/p75) in angiogenic signaling. METHODS AND RESULTS - We studied neovascularization in the hindlimb ischemia model in young and old TNFR2/p75 knockout (p75KO) and wild-type age-matched controls. Between days 7 to 10 after hindlimb surgery, 100% of old p75KOs experienced autoamputation of the operated limbs, whereas none of the age-matched wild-type mice exhibited hindlimb necrosis. Poor blood flow recovery in p75KO mice was associated with increased endothelial cell apoptosis, decreased capillary density, and significant reductions in the expression of vascular endothelial growth factor and basic fibroblast growth factor-2 mRNA transcripts in ischemic tissue and in circulating endothelial progenitor cells. The number of circulating bone marrow-derived endothelial progenitor cells was significantly reduced in p75KO mice. Transplantation of wild-type bone marrow mononuclear cells into irradiated old p75KO mice 1 month before hindlimb surgery prevented limb loss. CONCLUSIONS - Our present study suggests that ischemia-induced endothelial progenitor cell-mediated neovascularization is dependent, at least in part, on p75 TNF receptor expressed in bone marrow-derived cells. Specifically, endothelial cell/endothelial progenitor cell survival, vascular endothelial growth factor expression, endothelial progenitor cell mobilization from bone marrow, endothelial progenitor cell differentiation, and ultimately ischemia-induced collateral vessel development are dependent on signaling through TNFR2/p75. Furthermore, because TNFR2/p75 becomes an age-related limiting factor in postischemic recovery, it may be a potential gene target for therapeutic interventions in adult vascular diseases.

Original language	English (US)
Pages (from-to)	752-762
Number of pages	11
Journal	Circulation
Volume	115
Issue number	6
DOIs	https://doi.org/10.1161/CIRCULATIONAHA.106.647255
State	Published - Feb 2007

Keywords

Angiogenesis
Collateral circulation
Cytokines
Endothelium
Ischemia

ASJC Scopus subject areas

Cardiology and Cardiovascular Medicine
Physiology (medical)

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Goukassian, D. A., Qin, G., Dolan, C., Murayama, T., Silver, M., Curry, C., Eaton, E., Luedemann, C., Ma, H., Asahara, T., Zak, V., Mehta, S., Burg, A., Thorne, T., Kishore, R., & Losordo, D. W. (2007). Tumor necrosis factor-α receptor p75 is required in ischemia-induced neovascularization. Circulation, 115(6), 752-762. https://doi.org/10.1161/CIRCULATIONAHA.106.647255

Goukassian, David A. ; Qin, Gangjian ; Dolan, Christine ; Murayama, Toshinori ; Silver, Marcy ; Curry, Cynthia ; Eaton, Elizabeth ; Luedemann, Corinne ; Ma, Hong ; Asahara, Takayuki ; Zak, Victor ; Mehta, Shanu ; Burg, Aaron ; Thorne, Tina ; Kishore, Raj ; Losordo, Douglas W. / Tumor necrosis factor-α receptor p75 is required in ischemia-induced neovascularization. In: Circulation. 2007 ; Vol. 115, No. 6. pp. 752-762.

@article{b9295fdf03324b10b7e60e1c76c06bbb,

title = "Tumor necrosis factor-α receptor p75 is required in ischemia-induced neovascularization",

abstract = "BACKGROUND - Aging is a risk factor for coronary and peripheral artery disease. Tumor necrosis factor-α (TNF-α), a proinflammatory cytokine, is expressed in ischemic tissue and is known to modulate angiogenesis. Little is known about the role of TNF-α receptors (TNFR1/p55 and TNFR2/p75) in angiogenic signaling. METHODS AND RESULTS - We studied neovascularization in the hindlimb ischemia model in young and old TNFR2/p75 knockout (p75KO) and wild-type age-matched controls. Between days 7 to 10 after hindlimb surgery, 100% of old p75KOs experienced autoamputation of the operated limbs, whereas none of the age-matched wild-type mice exhibited hindlimb necrosis. Poor blood flow recovery in p75KO mice was associated with increased endothelial cell apoptosis, decreased capillary density, and significant reductions in the expression of vascular endothelial growth factor and basic fibroblast growth factor-2 mRNA transcripts in ischemic tissue and in circulating endothelial progenitor cells. The number of circulating bone marrow-derived endothelial progenitor cells was significantly reduced in p75KO mice. Transplantation of wild-type bone marrow mononuclear cells into irradiated old p75KO mice 1 month before hindlimb surgery prevented limb loss. CONCLUSIONS - Our present study suggests that ischemia-induced endothelial progenitor cell-mediated neovascularization is dependent, at least in part, on p75 TNF receptor expressed in bone marrow-derived cells. Specifically, endothelial cell/endothelial progenitor cell survival, vascular endothelial growth factor expression, endothelial progenitor cell mobilization from bone marrow, endothelial progenitor cell differentiation, and ultimately ischemia-induced collateral vessel development are dependent on signaling through TNFR2/p75. Furthermore, because TNFR2/p75 becomes an age-related limiting factor in postischemic recovery, it may be a potential gene target for therapeutic interventions in adult vascular diseases.",

keywords = "Angiogenesis, Collateral circulation, Cytokines, Endothelium, Ischemia",

author = "Goukassian, {David A.} and Gangjian Qin and Christine Dolan and Toshinori Murayama and Marcy Silver and Cynthia Curry and Elizabeth Eaton and Corinne Luedemann and Hong Ma and Takayuki Asahara and Victor Zak and Shanu Mehta and Aaron Burg and Tina Thorne and Raj Kishore and Losordo, {Douglas W.}",

year = "2007",

month = feb,

doi = "10.1161/CIRCULATIONAHA.106.647255",

language = "English (US)",

volume = "115",

pages = "752--762",

journal = "Circulation",

issn = "0009-7322",

publisher = "Lippincott Williams and Wilkins",

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Tumor necrosis factor-α receptor p75 is required in ischemia-induced neovascularization. / Goukassian, David A.; Qin, Gangjian; Dolan, Christine; Murayama, Toshinori; Silver, Marcy; Curry, Cynthia; Eaton, Elizabeth; Luedemann, Corinne; Ma, Hong; Asahara, Takayuki; Zak, Victor; Mehta, Shanu; Burg, Aaron; Thorne, Tina; Kishore, Raj; Losordo, Douglas W.

In: Circulation, Vol. 115, No. 6, 02.2007, p. 752-762.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Tumor necrosis factor-α receptor p75 is required in ischemia-induced neovascularization

AU - Goukassian, David A.

AU - Qin, Gangjian

AU - Dolan, Christine

AU - Murayama, Toshinori

AU - Silver, Marcy

AU - Curry, Cynthia

AU - Eaton, Elizabeth

AU - Luedemann, Corinne

AU - Ma, Hong

AU - Asahara, Takayuki

AU - Zak, Victor

AU - Mehta, Shanu

AU - Burg, Aaron

AU - Thorne, Tina

AU - Kishore, Raj

AU - Losordo, Douglas W.

PY - 2007/2

Y1 - 2007/2

N2 - BACKGROUND - Aging is a risk factor for coronary and peripheral artery disease. Tumor necrosis factor-α (TNF-α), a proinflammatory cytokine, is expressed in ischemic tissue and is known to modulate angiogenesis. Little is known about the role of TNF-α receptors (TNFR1/p55 and TNFR2/p75) in angiogenic signaling. METHODS AND RESULTS - We studied neovascularization in the hindlimb ischemia model in young and old TNFR2/p75 knockout (p75KO) and wild-type age-matched controls. Between days 7 to 10 after hindlimb surgery, 100% of old p75KOs experienced autoamputation of the operated limbs, whereas none of the age-matched wild-type mice exhibited hindlimb necrosis. Poor blood flow recovery in p75KO mice was associated with increased endothelial cell apoptosis, decreased capillary density, and significant reductions in the expression of vascular endothelial growth factor and basic fibroblast growth factor-2 mRNA transcripts in ischemic tissue and in circulating endothelial progenitor cells. The number of circulating bone marrow-derived endothelial progenitor cells was significantly reduced in p75KO mice. Transplantation of wild-type bone marrow mononuclear cells into irradiated old p75KO mice 1 month before hindlimb surgery prevented limb loss. CONCLUSIONS - Our present study suggests that ischemia-induced endothelial progenitor cell-mediated neovascularization is dependent, at least in part, on p75 TNF receptor expressed in bone marrow-derived cells. Specifically, endothelial cell/endothelial progenitor cell survival, vascular endothelial growth factor expression, endothelial progenitor cell mobilization from bone marrow, endothelial progenitor cell differentiation, and ultimately ischemia-induced collateral vessel development are dependent on signaling through TNFR2/p75. Furthermore, because TNFR2/p75 becomes an age-related limiting factor in postischemic recovery, it may be a potential gene target for therapeutic interventions in adult vascular diseases.

AB - BACKGROUND - Aging is a risk factor for coronary and peripheral artery disease. Tumor necrosis factor-α (TNF-α), a proinflammatory cytokine, is expressed in ischemic tissue and is known to modulate angiogenesis. Little is known about the role of TNF-α receptors (TNFR1/p55 and TNFR2/p75) in angiogenic signaling. METHODS AND RESULTS - We studied neovascularization in the hindlimb ischemia model in young and old TNFR2/p75 knockout (p75KO) and wild-type age-matched controls. Between days 7 to 10 after hindlimb surgery, 100% of old p75KOs experienced autoamputation of the operated limbs, whereas none of the age-matched wild-type mice exhibited hindlimb necrosis. Poor blood flow recovery in p75KO mice was associated with increased endothelial cell apoptosis, decreased capillary density, and significant reductions in the expression of vascular endothelial growth factor and basic fibroblast growth factor-2 mRNA transcripts in ischemic tissue and in circulating endothelial progenitor cells. The number of circulating bone marrow-derived endothelial progenitor cells was significantly reduced in p75KO mice. Transplantation of wild-type bone marrow mononuclear cells into irradiated old p75KO mice 1 month before hindlimb surgery prevented limb loss. CONCLUSIONS - Our present study suggests that ischemia-induced endothelial progenitor cell-mediated neovascularization is dependent, at least in part, on p75 TNF receptor expressed in bone marrow-derived cells. Specifically, endothelial cell/endothelial progenitor cell survival, vascular endothelial growth factor expression, endothelial progenitor cell mobilization from bone marrow, endothelial progenitor cell differentiation, and ultimately ischemia-induced collateral vessel development are dependent on signaling through TNFR2/p75. Furthermore, because TNFR2/p75 becomes an age-related limiting factor in postischemic recovery, it may be a potential gene target for therapeutic interventions in adult vascular diseases.

KW - Angiogenesis

KW - Collateral circulation

KW - Cytokines

KW - Endothelium

KW - Ischemia

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