Abstract
Forkhead box (Fox) transcription factors are important regulators of cardiovascular development and several Fox-proteins have recently been shown to modulate embryonic and post-natal angiogenesis. However, the role of the FoxP subfamily, which is highly expressed in cardiovascular tissue, has not been investigated so far. Here, we show that the transcription factor FoxP1 is the highest expressed FoxP-protein in endothelial cells and that it is upregulated at the site of neovascularization during hindlimb ischemia in mice. Silencing of FoxP1 results in a strong inhibition of proliferation, tube formation and migration of cultured endothelial cells. Accordingly, knockdown of FoxP1 in zebrafish was followed by a disruption of intersomitic vascular formation. Using gene expression profiling, we show that FoxP1 induces a specific change of the endothelial transcriptome and functions as a suppressor of semaphorin 5B, which has previously been described as a neuronal inhibitory factor. Our findings now demonstrate that semaphorin 5B also acts as a FoxP1- dependent suppressor of endothelial cell proliferation, migration and sprouting, mediating the effects of FoxP1. In summary, our data indicate that the transcription factor FoxP1 is essential for the angiogenic function of endothelial cells and functions as a suppressor of the inhibitory guidance cue semaphorin 5B, suggesting an important function of FoxP1 in the regulation of neovascularization.
Highlights
The development and growth of capillary and arterial blood vessels is a basic process in embryonic development as well as during physiological and pathophysiological processes in the adult organism, such as the neoplastic tumor growth, inflammation, wound healing and the adaptive response to tissue ischemia due to atherosclerotic vascular disease
Since FoxP1 is highly expressed in endothelial cells, we asked if this transcription factor is differentially expressed during vascular proliferation in vivo
As semaphorin 5B is well described as an inhibitory guidance cue for neuronal axons [19] and after we had confirmed its regulation by FoxP1, we investigated if this protein has an inhibitory effect on angiogenic functions of endothelial cells as well
Summary
The development and growth of capillary and arterial blood vessels is a basic process in embryonic development as well as during physiological and pathophysiological processes in the adult organism, such as the neoplastic tumor growth, inflammation, wound healing and the adaptive response to tissue ischemia due to atherosclerotic vascular disease. The regulation of these adaptive processes is a complex event, orchestrated by transcriptional factors that regulate the expression of both pro- and antiangiogenic genes [1]. Three families of Fox-proteins have been studied in the context of blood vessel development and neovascularization: the FoxO-family, FoxH1 and FoxC
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