Hemodynamic regulation of perivalvular endothelial gene expression prevents deep venous thrombosis

Welsh, John D.; Hoofnagle, Mark H.; Bamezai, Sharika; Oxendine, Michael; Lim, Lillian; Hall, Joshua D.; Yang, Jun; Schultz, Susan K.; Engel, James Douglas; Kume, Tsutomu; Oliver, Guillermo; Jiménez, Juan M.; Kahn, Mark L.

doi:10.1172/jci124791

Cited by 49 publications

(52 citation statements)

References 47 publications

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“…A clear correlation between haemodynamic forces and the inflammation‐coagulation axis was shown in the case of venous valves, where low or no shear (stasis) decreases shear activated transcription factors FOXC2 and Prox1 that control the expression of TM and EPCR, thus decreasing the anticoagulant potential while increasing leucocyte adhesion and inflammation 119 . If in early sepsis, the ECs could remain functional with an intact glycocalyx, adequate SS and mechanotransduction, they would likely show down‐regulation of both pro‐coagulant and pro‐inflammatory effects, thus impeding the autoamplification cycle (Figure 4A).…”

Section: Discussionmentioning

confidence: 98%

The role of endothelial shear stress on haemodynamics, inflammation, coagulation and glycocalyx during sepsis

Lupu

Kinasewitz

Dormer³

2020

J Cellular Molecular Medi

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Section: Discussionmentioning

confidence: 98%

The role of endothelial shear stress on haemodynamics, inflammation, coagulation and glycocalyx during sepsis

Lupu

Kinasewitz

Dormer³

2020

J Cellular Molecular Medi

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“…FOXC2 transcription factor plays an important role in human pathophysiology, both in genetics and in cancer [19,21,[28][29][30][31][32]. So far, about 110 different mutations along the entire gene have been described in LD patients, but little is known about their molecular consequences [4,17,26,27,33].…”

Section: Discussionmentioning

confidence: 99%

FOXC2 Disease Mutations Identified in Lymphedema Distichiasis Patients Impair Transcriptional Activity and Cell Proliferation

Tavian

Missaglia

Michelini

et al. 2020

IJMS

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FOXC2 is a member of the human forkhead-box gene family and encodes a regulatory transcription factor. Mutations in FOXC2 have been associated with lymphedema distichiasis (LD), an autosomal dominant disorder that primarily affects the limbs. Most patients also show extra eyelashes, a condition known as distichiasis. We previously reported genetic and clinical findings in six unrelated families with LD. Half the patients showed missense mutations, two carried frameshift mutations and a stop mutation was identified in a last patient. Here we analyzed the subcellular localization and transactivation activity of the mutant proteins, showing that all but one (p.Y109*) localized to the nucleus. A significant reduction of transactivation activity was observed in four mutants (p.L80F, p.H199Pfs*264, p.I213Tfs*18, p.Y109*) compared with wild type FOXC2 protein, while only a partial loss of function was associated with p.V228M. The mutant p.I213V showed a very slight increase of transactivation activity. Finally, immunofluorescence analysis revealed that some mutants were sequestered into nuclear aggregates and caused a reduction of cell viability. This study offers new insights into the effect of FOXC2 mutations on protein function and shows the involvement of aberrant aggregation of FOXC2 proteins in cell death.

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“…Because tissue factor, expressed locally at sites of vessel wall injury and from circulating monocytes [ 21 ] plays a pivotal role in the thrombotic phenotype of coronary atherosclerosis, an important surface protein antagonist, tissue factor pathway inhibitor (TFPI), has gained considerable attention. A variety of other surface proteins, including protein C, protein S, protein Z, nitric oxide, glycosaminoglycans, β2-glycoprotein 1, tissue plasminogen activator, urokinase-like plasminogen activator and thrombomodulin among others play critical roles [ 22 – 24 ].…”

Section: How Do Endothelial Cells Regulate Thrombosis?mentioning

confidence: 99%

COVID-19-associated vasculitis and vasculopathy

Becker

2020

J Thromb Thrombolysis

259

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The COVID-19 pandemic now totaling 13,000,000 cases and over 571,000 deaths has continued to teach the medical, scientific and lay communities about viral infectious disease in the modern era. Among the many lessons learned for the medical community is the potential for transmissibility and host infectivity of the SARS-CoV-2 virus. Moreover, it has become clear that the virus can affect any organ including the circulatory system, directly via either tissue tropism or indirectly stemming from inflammatory responses in the form of innate immunity, leukocyte debris such as cell-free DNA and histones and RNA viral particles. The following review considers COVID-19-associated vasculitis and vasculopathy as a defining feature of a virus-induced systemic disease with acute, subacute and potential chronic health implications.

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Hemodynamic regulation of perivalvular endothelial gene expression prevents deep venous thrombosis

Cited by 49 publications

References 47 publications

The role of endothelial shear stress on haemodynamics, inflammation, coagulation and glycocalyx during sepsis

The role of endothelial shear stress on haemodynamics, inflammation, coagulation and glycocalyx during sepsis

FOXC2 Disease Mutations Identified in Lymphedema Distichiasis Patients Impair Transcriptional Activity and Cell Proliferation

COVID-19-associated vasculitis and vasculopathy

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