FOXC2 Autoregulates Its Expression in the Pulmonary Endothelium After Endotoxin Stimulation in a Histone Acetylation-Dependent Manner

Sheng, Xia; Yu, Wei; Menden, Heather; Younger, Scott T.; Sampath, Venkatesh

doi:10.3389/fcell.2021.657662

Cited by 7 publications

(4 citation statements)

References 54 publications

(80 reference statements)

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“…Several transcription factors such as ERG (Lathen et al, 2014), FoxC (Xia et al, 2021), KLF2 (Atkins and Jain, 2007), Sox17 (Liu et al, 2019), and EGR1 (Akhter et al, 2021) are known to be involved in maintaining the barrier restrictive EC transcriptome. However, our findings identified KLF2 as the tension-regulated transcription factor using global ATAC-seq.…”

Section: Discussionmentioning

confidence: 99%

Tension sensing by FAK governs nuclear mechanotransduction, endothelial transcriptome and fate

Akhter

Yazbeck

Tauseef

et al. 2023

Preprint

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Vascular endothelium forms a restrictive barrier to defend the underlying tissue against uncontrolled influx of circulating protein and immune cells. Mechanisms that mediate the transition from restrictive to leaky endothelium, a hallmark of tissue injury exemplified by acute lung injury (ALI), remain elusive. Using endothelial cell (EC)-Fak-/- mice, we show that FAK sensing and transmission of mechanical tension to the EC nucleus governs cell fate. In FAK-deleted EC, increased EC tension induced by Rho kinase caused tyrosine phosphorylation of nuclear envelope protein, emerin at Y74/Y95, and its localization in a nuclear cap. Activated emerin stimulated DNMT3a activity and methylation of the KLF2 promoter, impairing the restrictive EC transcriptome, including S1PR1. Inhibiting emerin phosphorylation or DNMT3a activity enabled KLF2 transcription of S1PR1, rescuing the restrictive EC phenotype in EC-Fak-/- lungs. Thus, FAK sensing of tension transmission to the nucleus is crucial for maintaining a restrictive EC fate and lung homeostasis.

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Section: Discussionmentioning

confidence: 99%

Tension sensing by FAK governs nuclear mechanotransduction, endothelial transcriptome and fate

Akhter

Yazbeck

Tauseef

et al. 2023

Preprint

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“…PCR products were then sequentially digested, purified, ligated to vector pGL4.10 (#E6651; Promega, Madison, WI, USA) and cloned into TOP10 competent cells (#C404003; Thermo Fisher) to generate pGL4.10‐CLDN5 plasmids. pGL4.10 vector, pGL4.10‐CLDN5, pcDNA3.1 vector and pcDNA3‐NICD (WT) plasmids were co‐transfected into HEK293T cells (#11631017; Thermo Fisher) cultured and luciferase assay was performed as previously described (Guarani et al., 2011; Xia, Yu, et al., 2021; Yu et al., 2023). The experiment was conducted three times in total.…”

Section: Methodsmentioning

confidence: 99%

Delta like 4 regulates cerebrovascular development and endothelial integrity via DLL4‐NOTCH‐CLDN5 pathway and is vulnerable to neonatal hyperoxia

Ke,

Xia,

et al. 2024

The Journal of Physiology

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The mechanisms governing brain vascularization during development remain poorly understood. A key regulator of developmental vascularization is delta like 4 (DLL4), a Notch ligand prominently expressed in endothelial cells (EC). Exposure to hyperoxia in premature infants can disrupt the development and functions of cerebral blood vessels and lead to long‐term cognitive impairment. However, its role in cerebral vascular development and the impact of postnatal hyperoxia on DLL4 expression in mouse brain EC have not been explored. We determined the DLL4 expression pattern and its downstream signalling gene expression in brain EC using Dll4+/+ and Dll4+/LacZ mice. We also performed in vitro studies using human brain microvascular endothelial cells. Finally, we determined Dll4 and Cldn5 expression in mouse brain EC exposed to postnatal hyperoxia. DLL4 is expressed in various cell types, with EC being the predominant one in immature brains. Moreover, DLL4 deficiency leads to persistent abnormalities in brain microvasculature and increased vascular permeability both in vivo and in vitro. We have identified that DLL4 insufficiency compromises endothelial integrity through the NOTCH‐NICD‐RBPJ‐CLDN5 pathway, resulting in the downregulation of the tight junction protein claudin 5 (CLDN5). Finally, exposure to neonatal hyperoxia reduces DLL4 and CLDN5 expression in developing mouse brain EC. We reveal that DLL4 is indispensable for brain vascular development and maintaining the blood–brain barrier's function and is repressed by neonatal hyperoxia. We speculate that reduced DLL4 signalling in brain EC may contribute to the impaired brain development observed in neonates exposed to hyperoxia. imageKey points The role of delta like 4 (DLL4), a Notch ligand in vascular endothelial cells, in brain vascular development and functions remains unknown. We demonstrate that DLL4 is expressed at a high level during postnatal brain development in immature brains and DLL4 insufficiency leads to abnormal cerebral vasculature and increases vascular permeability both in vivo and in vitro. We identify that DLL4 regulates endothelial integrity through NOTCH‐NICD‐RBPJ‐CLDN5 signalling. Dll4 and Cldn5 expression are decreased in mouse brain endothelial cells exposed to postnatal hyperoxia.

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“…The ChIP experiment was performed as previously described (Xia et al , 2021). Briefly, the Human Umbilical Vein Endothelial Cells (HUVEC, ScienCell, #8000) and Human Dermal Lymphatic Endothelial Cells (HDLEC, PromoCell, C12216) were grown as seller's instructions and fixed with 1% formaldehyde for 12 min.…”

Section: Methodsmentioning

confidence: 99%

Endothelial FOXC1 and FOXC2 promote intestinal regeneration after ischemia–reperfusion injury

Tan,

Norden,

et al. 2023

EMBO Reports

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Intestinal ischemia underlies several clinical conditions and can result in the loss of the intestinal mucosal barrier. Ischemia‐induced damage to the intestinal epithelium is repaired by stimulation of intestinal stem cells (ISCs), and paracrine signaling from the vascular niche regulates intestinal regeneration. Here, we identify FOXC1 and FOXC2 as essential regulators of paracrine signaling in intestinal regeneration after ischemia–reperfusion (I/R) injury. Vascular endothelial cell (EC)‐ and lymphatic EC (LEC)‐specific deletions of Foxc1, Foxc2, or both in mice worsen I/R‐induced intestinal damage by causing defects in vascular regrowth, expression of chemokine CXCL12 and Wnt activator R‐spondin 3 (RSPO3) in blood ECs (BECs) and LECs, respectively, and activation of Wnt signaling in ISCs. Both FOXC1 and FOXC2 directly bind to regulatory elements of the CXCL12 and RSPO3 loci in BECs and LECs, respectively. Treatment with CXCL12 and RSPO3 rescues the I/R‐induced intestinal damage in EC‐ and LEC‐Foxc mutant mice, respectively. This study provides evidence that FOXC1 and FOXC2 are required for intestinal regeneration by stimulating paracrine CXCL12 and Wnt signaling.

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FOXC2 Autoregulates Its Expression in the Pulmonary Endothelium After Endotoxin Stimulation in a Histone Acetylation-Dependent Manner

Cited by 7 publications

References 54 publications

Tension sensing by FAK governs nuclear mechanotransduction, endothelial transcriptome and fate

Tension sensing by FAK governs nuclear mechanotransduction, endothelial transcriptome and fate

Delta like 4 regulates cerebrovascular development and endothelial integrity via DLL4‐NOTCH‐CLDN5 pathway and is vulnerable to neonatal hyperoxia

Endothelial FOXC1 and FOXC2 promote intestinal regeneration after ischemia–reperfusion injury

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