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Foxc2 transcription factor: a newly described regulator of angiogenesis.

ABSTRACT: Angiogenesis is a critical process to form new blood vessels from preexisting vessels under physiologic and pathologic conditions and involves cellular and morphologic changes such as endothelial cell proliferation, migration, and vascular tube formation. Despite evidence that angiogenic factors, including vascular endothelial growth factor and Notch, control various aspects of angiogenesis, the molecular mechanisms underlying gene regulation in blood vessels and surrounding tissues are not fully understood. Importantly, recent studies demonstrate that Forkhead transcription factor Foxc2 directly regulates expression of various genes involved in angiogenesis, CXCR4, integrin beta3, Delta-like 4 (Dll4), and angiopoietin 2, thereby controlling angiogenic processes. Thus, Foxc2 is now recognized as a novel regulator of vascular formation and remodeling. This review summarizes current knowledge about the function of Foxc2 in angiogenesis and discusses prospects for future research in Foxc2-mediated pathologic angiogenesis in cardiovascular disease.

SUBMITTER: Kume T

PROVIDER: S-EPMC2674371 | biostudies-literature | 2008 Aug

REPOSITORIES: biostudies-literature

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Foxc2 transcription factor: a newly described regulator of angiogenesis.

Kume Tsutomu T

Trends in cardiovascular medicine 20080801 6

Angiogenesis is a critical process to form new blood vessels from preexisting vessels under physiologic and pathologic conditions and involves cellular and morphologic changes such as endothelial cell proliferation, migration, and vascular tube formation. Despite evidence that angiogenic factors, including vascular endothelial growth factor and Notch, control various aspects of angiogenesis, the molecular mechanisms underlying gene regulation in blood vessels and surrounding tissues are not full ...[more]

PMID: 19185813

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Project description:RATIONALE:Postischemic angiogenesis is critical to limit the ischemic tissue damage and improve the blood flow recovery. The regulation and the underlying molecular mechanisms of postischemic angiogenesis are not fully unraveled. TFEB (transcription factor EB) is emerging as a master gene for autophagy and lysosome biogenesis. However, the role of TFEB in vascular disease is less understood. OBJECTIVE:We aimed to determine the role of endothelial TFEB in postischemic angiogenesis and its underlying molecular mechanism. METHODS AND RESULTS:In primary human endothelial cells (ECs), serum starvation induced TFEB nuclear translocation. VEGF (vascular endothelial growth factor) increased TFEB expression level and nuclear translocation. Utilizing genetically engineered EC-specific TFEB transgenic and KO (knockout) mice, we investigated the role of TFEB in postischemic angiogenesis in the mouse hindlimb ischemia model. We observed improved blood perfusion and increased capillary density in the EC-specific TFEB transgenic mice compared with the wild-type littermates. Furthermore, blood flow recovery was attenuated in EC-TFEB KO mice compared with control mice. In aortic ring cultures, the TFEB transgene significantly increased vessel sprouting, whereas TFEB deficiency impaired the vessel sprouting. In vitro, adenovirus-mediated TFEB overexpression promoted EC tube formation, migration, and survival, whereas siRNA-mediated TFEB knockdown had the opposite effect. Mechanistically, TFEB activated AMPK (AMP-activated protein kinase)-? signaling and upregulated autophagy. Through inactivation of AMPK? or inhibition of autophagy, we demonstrated that the AMPK? and autophagy are necessary for TFEB to regulate angiogenesis in ECs. Finally, the positive effect of TFEB on AMPK? activation and EC tube formation was mediated by TFEB-dependent transcriptional upregulation of MCOLN1 (mucolipin-1). CONCLUSIONS:In summary, our data demonstrate that TFEB is a positive regulator of angiogenesis through activation of AMPK? and autophagy, suggesting that TFEB constitutes a novel molecular target for ischemic vascular disease.

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Foxc2 transcription factor: a newly described regulator of angiogenesis.

Publications

Foxc2 transcription factor: a newly described regulator of angiogenesis.

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