Human venous valve disease caused by mutations in <i>FOXC2</i> and <i>GJC2</i>

Lyons, Oliver; Saha, Prakash; Seet, Christopher; Kuchta, Adam; Arnold, Andrew J.; Grover, Steven P.; Rashbrook, Victoria S.; Sabine, Amélie; Vizcay‐Barrena, Gema; Patel, Ashish; Ludwinski, Francesca; Padayachee, Soundrie; Kume, Tsutomu; Kwak, Brenda R.; Brice, Glen; Mansour, Sahar; Østergaard, Pia; Mortimer, Peter; Jeffery, Steve; Brown, Nigel A.; Mäkinen, Taija; Petrova, Tatiana V.; Modarai, Bijan; Smith, Alberto

doi:10.1084/jem.20160875

Cited by 30 publications

(72 citation statements)

References 55 publications

(135 reference statements)

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“…The Ca 2+ /NFAT signaling pathway is a crucial signaling pathway for maintaining the normal physiological functions of the cardiovascular system as well as pathophysiology. Studies have reported that the Ca 2+ /NFAT signaling pathway is essential for coronary angiogenesis and venous valves development during vascular plexus formation [37][38][39] . Reports have shown that the NFAT pathway may be the main signaling Supplementary Fig.…”

Section: Discussionmentioning

confidence: 99%

The role of Ca2+/NFAT in Dysfunction and Inflammation of Human Coronary Endothelial Cells induced by Sera from patients with Kawasaki disease

Wang

Liu

et al. 2020

Sci Rep

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ca 2+ /nuclear factor of activated t-cells (ca 2+ /NFAT) signaling pathway may play a crucial role in the pathogenesis of Kawasaki disease (KD). We investigated the poorly understood Ca 2+ /nfAt regulation of coronary artery endothelial cells and consequent dysfunction in KD pathogenesis. Human coronary artery endothelial cells (HCAECs) stimulated with sera from patients with KD, compared with sera from healthy children, exhibited significant increases in proliferation and angiogenesis, higher levels of NFATc1 and NFATc3 and some inflammatory molecules, and increased nuclear translocation of NFATc1 and NFATc3. HCAECs stimulated with sera from patients with KD treated with cyclosporine A (CsA) showed decreased proliferation, angiogenesis, NFATc1 and inflammatory molecules levels as compared with results for untreated HCAECs. In conclusion, our data reveal that KD sera activate the Ca 2+ /nfAt in HCAECs, leading to dysfunction and inflammation of endothelial cells. CsA has cytoprotective effects by ameliorating endothelial cell homeostasis via Ca 2+ /NFAT. Kawasaki Disease (KD), also known as mucocutaneous lymph node syndrome (MCLS), is an acute febrile rash that occurs mainly in children under 5 years which is the most common systemic vasculitis syndrome in children 1 . The disease mainly affects small and medium arteries, especially coronary arteries. Coronary artery lesions (CAL) can occur in 25% of patients 2 . Coronary artery injury and coronary aneurysm formation are the most important acute and long-term sequela of KD 3,4 .The pathogenesis of KD remains unclear. Recent studies have confirmed that vascular endothelial cells (VECs) play a very important role in the coronary artery injury of KD 5 . Children with KD have abnormal activation of the immune system; VECs are stimulated to express and release a variety of adhesion factors, which in turn cause inflammatory cells to adhere to the surface of endothelial cells, which resulting in inflammation to damage of VECs 6 . The dysfunction of VECs plays a vital role in vascular tension, lipid metabolism and coagulation mechanism, which in turn activate inflammatory cells, causing inflammation extending deep into the endothelium, leading to destruction of the vascular elastic layer, formation of coronary aneurysm and vascular remodeling 7 .

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Section: Discussionmentioning

confidence: 99%

The role of Ca2+/NFAT in Dysfunction and Inflammation of Human Coronary Endothelial Cells induced by Sera from patients with Kawasaki disease

Wang

Liu

et al. 2020

Sci Rep

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“…The observed discrepancy between intracellular and surface P-selectin expression is consis-through upregulation of the FOXC2, GATA2, and PROX1 transcription factors in perivalvular endothelial cells (11)(12)(13)(14)(15)(16)(17), and sustained expression of FOXC2 and GATA2 is required to maintain lymphatic valves in the mature animal (16,18). Since venous valves are morphologically identical to lymphatic valves and also require FOXC2 and PROX1 to develop (19)(20)(21)(22), we assessed whether this transcriptional program might be maintained in the endothelium surrounding the mature venous valve. Immunostaining of mouse saphenous veins from wild-type animals and PROX1-GFP transgenic reporter animals revealed that FOXC2 and PROX1 were specifically expressed in endothelial cells lining both sides of the venous valve and the adjacent valve sinus, but were undetectable in nonvalvular, lumenal venous endothelium ( Figure 1, A and B).…”

Section: Perivalvular Venous Endothelial Cells Express Foxc2 and Prox1mentioning

confidence: 99%

Hemodynamic regulation of perivalvular endothelial gene expression prevents deep venous thrombosis

Welsh¹,

Hoofnagle²,

Bamezai³

et al. 2019

Journal of Clinical Investigation

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“…It has recently been reported that human venous valve disease may be caused by mutations in the GJC2 gene. Patients with such mutation show reduced number and length of venous valves (20). Interestingly, Cx47 −/− mice display disrupted organization and reduced proliferation of venous valve-forming ECs, which may underlie the venous valve defects seen in patients with GJC2 mutations (20).…”

Section: Connexins In Lymphatic Edemamentioning

confidence: 99%

“…Patients with such mutation show reduced number and length of venous valves (20). Interestingly, Cx47 −/− mice display disrupted organization and reduced proliferation of venous valve-forming ECs, which may underlie the venous valve defects seen in patients with GJC2 mutations (20). Comparable changes in venous valve-forming ECs were observed in Cx37 −/− and Cx43 −/− mouse embryos, suggesting that it might be relevant to search for mutations in GJA4 and GJA1 genes in venous valve disease patients.…”

Section: Connexins In Lymphatic Edemamentioning

confidence: 99%

Endothelial connexins in vascular function

2019

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Gap junctions are essential for intercellular crosstalk in blood and lymphatic vasculature. These clusters of intercellular channels ensure direct communication among endothelial cells and between endothelial and smooth muscle cells, and the synchronization of their behavior along the vascular tree. Gap junction channels are formed by connexins; six connexins form a connexon or hemichannel and the docking of two connexons result in a full gap junction channel allowing for the exchange of ions and small metabolites between neighboring cells. Recent evidence indicates that the intracellular domains of connexins may also function as an interaction platform (interactome) for other proteins, thereby regulating their function. Interestingly, fragments of Cx proteins generated by alternative internal translation were recently described, although their functions in the vascular wall remain to be uncovered. Variations in connexin expression are observed along different types of blood and lymphatic vessels; the most commonly found endothelial connexins are Cx37, Cx40, Cx43 and Cx47. Physiological studies on connexin-knockout mice demonstrated the essential roles of these channel-forming proteins in the coordination of vasomotor activity, endothelial permeability and inflammation, angiogenesis and in the maintenance of fluid balance in the body.

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Human venous valve disease caused by mutations in FOXC2 and GJC2

Cited by 30 publications

References 55 publications

The role of Ca2+/NFAT in Dysfunction and Inflammation of Human Coronary Endothelial Cells induced by Sera from patients with Kawasaki disease

The role of Ca2+/NFAT in Dysfunction and Inflammation of Human Coronary Endothelial Cells induced by Sera from patients with Kawasaki disease

Hemodynamic regulation of perivalvular endothelial gene expression prevents deep venous thrombosis

Endothelial connexins in vascular function

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