Studies on Axenfeld–Rieger syndrome patients and mice reveal Foxc1's role in corneal neovascularization

François, Mathias; Ramchandran, Ramani

doi:10.1073/pnas.1119291109

Cited by 3 publications

(2 citation statements)

References 16 publications

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“…Like FoxC1, the SOX (SRY [sex determining region Y]-related HMG [high mobility group]-box) transcription factors are crucially involved in vascular development, and abnormal corneal vascularity has been observed in mice heterozygous for the Ragged Opossum (Ra Op ) mutation (Francois and Ramchandran, 2012), which is a dominant-negative Sox18 truncation that is believed to suppress the function of F-group SOX members (Sox7, Sox17, and Sox18) (Francois et al, 2008; James et al, 2003). Thus, the SoxF transcription factors may also function as angiogenic inhibitors in the developing cornea, but whether SoxF interacts synergistically with FoxC1 or must be expressed in the NC-derived corneal stroma to maintain corneal transparency has yet to be determined.…”

Section: Foxc1 and Corneal Vessel Growthmentioning

confidence: 99%

FoxC1-Dependent Regulation of Vascular Endothelial Growth Factor Signaling in Corneal Avascularity

Koo

Kume

2013

Trends in Cardiovascular Medicine

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Angiogenesis is a crucial process whereby new blood vessels are formed from pre-existing vessels and occurs under both normal and pathophysiological conditions. The process is precisely regulated through the balance between pro-angiogenic and anti-angiogenic mechanisms, and many of these mechanisms have been well-characterized through extensive research; however, little is known about how angiogenesis is regulated at the transcriptional level. We have recently shown that deletion of the Forkhead box (Fox) transcription factor Foxc1 in cells of neural crest (NC) lineage leads to aberrant vessel growth in the normally avascular corneas of mice, and that the effect is cell-type specific, because the corneas of mice lacking Foxc1 expression in vascular endothelial cells remained avascular. The NC-specific Foxc1 deletion was also associated with elevated levels of both pro-angiogenic factors, such as the matrix metalloproteases (MMPs) MMP-3, MMP-9, and MMP-19, and the angiogenic inhibitor soluble vascular endothelial growth factor receptor 1 (sVEGFR-1). Thus, FoxC1 appears to control angiogenesis by regulating two distinct and opposing mechanisms; if so, vascular development could be determined, at least in part, by a competitive balance between pro-angiogenic and anti-angiogenic FoxC1-regulated pathways. In this review, we describe the mechanisms by which FoxC1 regulates vessel growth and discuss how these observations could contribute to a more complete understanding of the role of FoxC1 in pathological angiogenesis.

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Section: Foxc1 and Corneal Vessel Growthmentioning

confidence: 99%

FoxC1-Dependent Regulation of Vascular Endothelial Growth Factor Signaling in Corneal Avascularity

Koo

Kume

2013

Trends in Cardiovascular Medicine

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“…This mouse mutant is considered a murine counterpart of human HLTRS syndrome since it displays the same range of cardio-vascular and hair follicle defects and exhibits the same type of dominant-negative mutation in the Sox18 gene (Pennisi et al, 2000; Downes et al, 2009; François et al, 2008; Villani et al, 2017). The Ragged mouse is characterized by pathologic corneal neo-vascularisation (CNV, Figure 2—figure supplement 1A-C) (François and Ramchandran, 2012). This phenotypic hallmark offers an indirect biological readout in vivo for aberrant SOX18 function in the control of vessel outgrowth.…”

Section: Resultsmentioning

confidence: 99%

R-propranolol is a small molecule inhibitor of the SOX18 transcription factor in a rare vascular syndrome and hemangioma

Overman

Fontaine

Wylie-Sears

et al. 2019

eLife

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Propranolol is an approved non-selective β-adrenergic blocker that is first line therapy for infantile hemangioma. Despite the clinical benefit of propranolol therapy in hemangioma, the mechanistic understanding of what drives this outcome is limited. Here, we report successful treatment of pericardial edema with propranolol in a patient with Hypotrichosis-Lymphedema-Telangiectasia and Renal (HLTRS) syndrome, caused by a mutation in SOX18. Using a mouse pre-clinical model of HLTRS, we show that propranolol treatment rescues its corneal neo-vascularisation phenotype. Dissection of the molecular mechanism identified the R(+)-propranolol enantiomer as a small molecule inhibitor of the SOX18 transcription factor, independent of any anti-adrenergic effect. Lastly, in a patient-derived in vitro model of infantile hemangioma and pre-clinical model of HLTRS we demonstrate the therapeutic potential of the R(+) enantiomer. Our work emphasizes the importance of SOX18 etiological role in vascular neoplasms, and suggests R(+)-propranolol repurposing to numerous indications ranging from vascular diseases to metastatic cancer.

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Wholemount imaging reveals abnormalities of the aqueous outflow pathway and corneal vascularity in Foxc1 and Bmp4 heterozygous mice

Merwe

Kidson

2016

Experimental Eye Research

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Studies on Axenfeld–Rieger syndrome patients and mice reveal Foxc1's role in corneal neovascularization

Cited by 3 publications

References 16 publications

FoxC1-Dependent Regulation of Vascular Endothelial Growth Factor Signaling in Corneal Avascularity

FoxC1-Dependent Regulation of Vascular Endothelial Growth Factor Signaling in Corneal Avascularity

R-propranolol is a small molecule inhibitor of the SOX18 transcription factor in a rare vascular syndrome and hemangioma

Wholemount imaging reveals abnormalities of the aqueous outflow pathway and corneal vascularity in Foxc1 and Bmp4 heterozygous mice

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