FKBPL Is a Critical Antiangiogenic Regulator of Developmental and Pathological Angiogenesis

Anita Yakkundi, Rachel Bennett, Ivette Hernández-Negrete, Jean-Marie Delalande, Mary Hanna, Oksana Lyubomska, Kenneth Arthur, Amy Short, Hayley McKeen, Laura Nelson, Cian M. McCrudden, Ross McNally, Lana McClements, Helen O McCarthy, Alan J. Burns, Roy Bicknell, Adrien Kissenpfennig, Tracy Robson

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Abstract

OBJECTIVE: The antitumor effects of FK506-binding protein like (FKBPL) and its extracellular role in angiogenesis are well characterized; however, its role in physiological/developmental angiogenesis and the effect of FKBPL ablation has not been evaluated. This is important as effects of some angiogenic proteins are dosage dependent. Here we evaluate the regulation of FKBPL secretion under angiogenic stimuli, as well as the effect of FKBPL ablation in angiogenesis using mouse and zebrafish models.

APPROACH AND RESULTS: FKBPL is secreted maximally by human microvascular endothelial cells and fibroblasts, and this was specifically downregulated by proangiogenic hypoxic signals, but not by the angiogenic cytokines, VEGF or IL8. FKBPL's critical role in angiogenesis was supported by our inability to generate an Fkbpl knockout mouse, with embryonic lethality occurring before E8.5. However, whilst Fkbpl heterozygotic embryos showed some vasculature irregularities, the mice developed normally. In murine angiogenesis models, including the ex vivo aortic ring assay, in vivo sponge assay, and tumor growth assay, Fkbpl(+/-) mice exhibited increased sprouting, enhanced vessel recruitment, and faster tumor growth, respectively, supporting the antiangiogenic function of FKBPL. In zebrafish, knockdown of zFkbpl using morpholinos disrupted the vasculature, and the phenotype was rescued with hFKBPL. Interestingly, this vessel disruption was ineffective when zcd44 was knocked-down, supporting the dependency of zFkbpl on zCd44 in zebrafish.

CONCLUSIONS: FKBPL is an important regulator of angiogenesis, having an essential role in murine and zebrafish blood vessel development. Mouse models of angiogenesis demonstrated a proangiogenic phenotype in Fkbpl heterozygotes.

Original languageEnglish
Pages (from-to)845-854
Number of pages10
JournalArteriosclerosis Thrombosis and Vascular Biology
Volume35
Early online date12 Mar 2015
DOIs
Publication statusPublished - Apr 2015

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Pathologic Neovascularization
Tacrolimus Binding Proteins
Zebrafish
Physiologic Neovascularization
Angiogenic Proteins
Phenotype
Morpholinos
Angiogenesis Inducing Agents
Porifera
Heterozygote
Growth
Interleukin-8
Knockout Mice
Vascular Endothelial Growth Factor A
Blood Vessels
Neoplasms
Down-Regulation
Embryonic Structures
Endothelial Cells
Fibroblasts

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Yakkundi, Anita ; Bennett, Rachel ; Hernández-Negrete, Ivette ; Delalande, Jean-Marie ; Hanna, Mary ; Lyubomska, Oksana ; Arthur, Kenneth ; Short, Amy ; McKeen, Hayley ; Nelson, Laura ; McCrudden, Cian M. ; McNally, Ross ; McClements, Lana ; McCarthy, Helen O ; Burns, Alan J. ; Bicknell, Roy ; Kissenpfennig, Adrien ; Robson, Tracy. / FKBPL Is a Critical Antiangiogenic Regulator of Developmental and Pathological Angiogenesis. In: Arteriosclerosis Thrombosis and Vascular Biology. 2015 ; Vol. 35. pp. 845-854.
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abstract = "OBJECTIVE: The antitumor effects of FK506-binding protein like (FKBPL) and its extracellular role in angiogenesis are well characterized; however, its role in physiological/developmental angiogenesis and the effect of FKBPL ablation has not been evaluated. This is important as effects of some angiogenic proteins are dosage dependent. Here we evaluate the regulation of FKBPL secretion under angiogenic stimuli, as well as the effect of FKBPL ablation in angiogenesis using mouse and zebrafish models.APPROACH AND RESULTS: FKBPL is secreted maximally by human microvascular endothelial cells and fibroblasts, and this was specifically downregulated by proangiogenic hypoxic signals, but not by the angiogenic cytokines, VEGF or IL8. FKBPL's critical role in angiogenesis was supported by our inability to generate an Fkbpl knockout mouse, with embryonic lethality occurring before E8.5. However, whilst Fkbpl heterozygotic embryos showed some vasculature irregularities, the mice developed normally. In murine angiogenesis models, including the ex vivo aortic ring assay, in vivo sponge assay, and tumor growth assay, Fkbpl(+/-) mice exhibited increased sprouting, enhanced vessel recruitment, and faster tumor growth, respectively, supporting the antiangiogenic function of FKBPL. In zebrafish, knockdown of zFkbpl using morpholinos disrupted the vasculature, and the phenotype was rescued with hFKBPL. Interestingly, this vessel disruption was ineffective when zcd44 was knocked-down, supporting the dependency of zFkbpl on zCd44 in zebrafish.CONCLUSIONS: FKBPL is an important regulator of angiogenesis, having an essential role in murine and zebrafish blood vessel development. Mouse models of angiogenesis demonstrated a proangiogenic phenotype in Fkbpl heterozygotes.",
author = "Anita Yakkundi and Rachel Bennett and Ivette Hern{\'a}ndez-Negrete and Jean-Marie Delalande and Mary Hanna and Oksana Lyubomska and Kenneth Arthur and Amy Short and Hayley McKeen and Laura Nelson and McCrudden, {Cian M.} and Ross McNally and Lana McClements and McCarthy, {Helen O} and Burns, {Alan J.} and Roy Bicknell and Adrien Kissenpfennig and Tracy Robson",
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Yakkundi, A, Bennett, R, Hernández-Negrete, I, Delalande, J-M, Hanna, M, Lyubomska, O, Arthur, K, Short, A, McKeen, H, Nelson, L, McCrudden, CM, McNally, R, McClements, L, McCarthy, HO, Burns, AJ, Bicknell, R, Kissenpfennig, A & Robson, T 2015, 'FKBPL Is a Critical Antiangiogenic Regulator of Developmental and Pathological Angiogenesis', Arteriosclerosis Thrombosis and Vascular Biology, vol. 35, pp. 845-854. https://doi.org/10.1161/ATVBAHA.114.304539

FKBPL Is a Critical Antiangiogenic Regulator of Developmental and Pathological Angiogenesis. / Yakkundi, Anita; Bennett, Rachel; Hernández-Negrete, Ivette; Delalande, Jean-Marie; Hanna, Mary; Lyubomska, Oksana; Arthur, Kenneth; Short, Amy; McKeen, Hayley; Nelson, Laura; McCrudden, Cian M.; McNally, Ross; McClements, Lana; McCarthy, Helen O; Burns, Alan J.; Bicknell, Roy; Kissenpfennig, Adrien; Robson, Tracy.

In: Arteriosclerosis Thrombosis and Vascular Biology, Vol. 35, 04.2015, p. 845-854.

Research output: Contribution to journalArticle

TY - JOUR

T1 - FKBPL Is a Critical Antiangiogenic Regulator of Developmental and Pathological Angiogenesis

AU - Yakkundi, Anita

AU - Bennett, Rachel

AU - Hernández-Negrete, Ivette

AU - Delalande, Jean-Marie

AU - Hanna, Mary

AU - Lyubomska, Oksana

AU - Arthur, Kenneth

AU - Short, Amy

AU - McKeen, Hayley

AU - Nelson, Laura

AU - McCrudden, Cian M.

AU - McNally, Ross

AU - McClements, Lana

AU - McCarthy, Helen O

AU - Burns, Alan J.

AU - Bicknell, Roy

AU - Kissenpfennig, Adrien

AU - Robson, Tracy

PY - 2015/4

Y1 - 2015/4

N2 - OBJECTIVE: The antitumor effects of FK506-binding protein like (FKBPL) and its extracellular role in angiogenesis are well characterized; however, its role in physiological/developmental angiogenesis and the effect of FKBPL ablation has not been evaluated. This is important as effects of some angiogenic proteins are dosage dependent. Here we evaluate the regulation of FKBPL secretion under angiogenic stimuli, as well as the effect of FKBPL ablation in angiogenesis using mouse and zebrafish models.APPROACH AND RESULTS: FKBPL is secreted maximally by human microvascular endothelial cells and fibroblasts, and this was specifically downregulated by proangiogenic hypoxic signals, but not by the angiogenic cytokines, VEGF or IL8. FKBPL's critical role in angiogenesis was supported by our inability to generate an Fkbpl knockout mouse, with embryonic lethality occurring before E8.5. However, whilst Fkbpl heterozygotic embryos showed some vasculature irregularities, the mice developed normally. In murine angiogenesis models, including the ex vivo aortic ring assay, in vivo sponge assay, and tumor growth assay, Fkbpl(+/-) mice exhibited increased sprouting, enhanced vessel recruitment, and faster tumor growth, respectively, supporting the antiangiogenic function of FKBPL. In zebrafish, knockdown of zFkbpl using morpholinos disrupted the vasculature, and the phenotype was rescued with hFKBPL. Interestingly, this vessel disruption was ineffective when zcd44 was knocked-down, supporting the dependency of zFkbpl on zCd44 in zebrafish.CONCLUSIONS: FKBPL is an important regulator of angiogenesis, having an essential role in murine and zebrafish blood vessel development. Mouse models of angiogenesis demonstrated a proangiogenic phenotype in Fkbpl heterozygotes.

AB - OBJECTIVE: The antitumor effects of FK506-binding protein like (FKBPL) and its extracellular role in angiogenesis are well characterized; however, its role in physiological/developmental angiogenesis and the effect of FKBPL ablation has not been evaluated. This is important as effects of some angiogenic proteins are dosage dependent. Here we evaluate the regulation of FKBPL secretion under angiogenic stimuli, as well as the effect of FKBPL ablation in angiogenesis using mouse and zebrafish models.APPROACH AND RESULTS: FKBPL is secreted maximally by human microvascular endothelial cells and fibroblasts, and this was specifically downregulated by proangiogenic hypoxic signals, but not by the angiogenic cytokines, VEGF or IL8. FKBPL's critical role in angiogenesis was supported by our inability to generate an Fkbpl knockout mouse, with embryonic lethality occurring before E8.5. However, whilst Fkbpl heterozygotic embryos showed some vasculature irregularities, the mice developed normally. In murine angiogenesis models, including the ex vivo aortic ring assay, in vivo sponge assay, and tumor growth assay, Fkbpl(+/-) mice exhibited increased sprouting, enhanced vessel recruitment, and faster tumor growth, respectively, supporting the antiangiogenic function of FKBPL. In zebrafish, knockdown of zFkbpl using morpholinos disrupted the vasculature, and the phenotype was rescued with hFKBPL. Interestingly, this vessel disruption was ineffective when zcd44 was knocked-down, supporting the dependency of zFkbpl on zCd44 in zebrafish.CONCLUSIONS: FKBPL is an important regulator of angiogenesis, having an essential role in murine and zebrafish blood vessel development. Mouse models of angiogenesis demonstrated a proangiogenic phenotype in Fkbpl heterozygotes.

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DO - 10.1161/ATVBAHA.114.304539

M3 - Article

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JO - Arteriosclerosis Thrombosis and Vascular Biology

JF - Arteriosclerosis Thrombosis and Vascular Biology

SN - 1079-5642

ER -