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.

Figure 1

Foxc2 regulates integrin β3 expression and microvessel outgrowth. (A) Surface levels of integrin β3 protein in pulmonary microvascular endothelial cells isolated from wild-type and Foxc2+/- mice measured by flow cytometry. Replicate analyses of independently isolated cells for each genotype are shown. (B) Aortic ring assay using adult aortas wild-type and Foxc2+/- mice. Data are presented as the relative number of microvessels sprouting from aortic rings. Results are presented as the means ± S.D. (n = 9 or more). P values were determined by the corresponding sample indicated using Student's t test. *, P < 0.05 versus the corresponding control. Adapted from Hayashi et al. (2008).

Figure 2

Mechanisms of Foxc2 function in vascular network formation. In vascular endothelial cells, Foxc2 directly regulates expression of integrin β3, CXCR4 and Dll4 by activating their promoters. While integrin αvβ3 interacts with extracellular matrix (ECM), CXCR4 binds to the CXCL12 ligand to induce endothelial cell migration and tube formation. Upon binding to Notch receptors, Dll4 regulates arterial cell identity and angiogenic sprouting. In contrast, Foxc2 induces Ang-2 expression in adipocytes thereby modulating angiogenesis and vascular maturation via activation of the Tie2 tyrosine kinase receptor on endothelial cells.