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

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)
204 Downloads (Pure)

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

Fingerprint Dive into the research topics of 'FKBPL Is a Critical Antiangiogenic Regulator of Developmental and Pathological Angiogenesis'. Together they form a unique fingerprint.

Cite this