Signaling Network Map of Endothelial TEK Tyrosine Kinase

Khan, Aafaque Ahmad; Sandhya, Varot K.; Singh, Priyata; Parthasarathy, Deepak; Kumar, Awinav; Advani, Jayshree; Gattu, Rudrappa; Ranjit, Dhanya V.; Vaidyanathan, Rama; Mathur, P. B.; Prasad, T. S. Keshava; Gabhann, Feilim Mac; Pandey, Akhilesh; Raju, Rajesh; Gowda, Harsha

doi:10.1155/2014/173026

Cited by 30 publications

(26 citation statements)

References 45 publications

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“…Herein, we observed aberrant methylation of several EGF-like factors ( TEK and LAMA3 ) in disease, further supporting disrupted EGF signaling in eutopic endometrium of women with endometriosis. TEK (tyrosine kinase, endothelial) plays a role in angiogenesis [41] and is more methylated in PE in disease versus controls, with decreased expression. LAMA3 (Laminin, alpha 3), an extracellular matrix component of basement membranes promoting epithelial cell attachment, migration, and organization [42], is less methylated and more expressed in MSE in disease versus control.…”

Section: Discussionmentioning

confidence: 99%

Aberrant Endometrial DNA Methylome and Associated Gene Expression in Women with Endometriosis

Houshdaran

Nezhat

et al. 2016

Biology of Reproduction

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Endometriosis is an estrogen-dependent, progesterone-resistant disorder largely derived from retrograde transplantation of menstrual tissue/cells into the pelvis, eliciting an inflammatory response, pelvic pain, and infertility. Eutopic endometrium (within the uterus), giving rise to pelvic disease, displays cycle-dependent transcriptomic, proteomic, and signaling abnormalities, and although its DNA methylation profiles dynamically change across the cycle in healthy women, studies in endometriosis are limited. Herein, we investigated the DNA methylome and associated gene expression in three phases of the cycle in eutopic endometrium of women with severe endometriosis versus controls, matched for ethnicity, medications, smoking, and no recent contraceptive steroid use. Genome-wide DNA methylation and gene expression were coassessed in each sample. Cycle phase was determined by histology, serum hormone levels, and unsupervised principal component and hierarchical cluster analyses of microarray data. Altered endometrial DNA methylation in endometriosis was most prominent in the midsecretory phase (peak progesterone), with disruption of the normal pattern of cycle-dependent DNA methylation changes, including a bias toward methylation of CpG islands, suggesting wide-range abnormalities of the chromatin remodeling machinery in endometriosis. DNA methylation changes were associated with altered gene expression relevant to endometrial function/dysfunction, including cell proliferation, inflammation/immune response, angiogenesis, and steroid hormone response. The data provide insight into epigenetic reprogramming and steroid hormone actions in endometrium contributing to the pathogenesis and pathophysiology of endometriosis.

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Section: Discussionmentioning

confidence: 99%

Aberrant Endometrial DNA Methylome and Associated Gene Expression in Women with Endometriosis

Houshdaran

Nezhat

et al. 2016

Biology of Reproduction

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“…The upregulation of LGALS1 in the presence of minocycline may have contributed to increased ECM attachment that could facilitate migration, and may have contributed to increased angiogenesis seen in HUVECs cultured with media conditioned from MSCs in hydrogels treated with minocyline. TEK is a tyrosine kinase receptor that can lead to proliferation through growth factor binding and is known to induce angiogenesis in endothelial cells when bound to growth factors [53]. The increased MSC VEGF secretion induced by minocycline may have contributed an autocrine effect on the increased TEK expressed receptors that could lead to increased proliferation of MSCs after culture with minocycline, as the receptor responds to growth factor binding to induce downstream signaling that can lead to proliferation [53].…”

Section: Discussionmentioning

confidence: 99%

“…TEK is a tyrosine kinase receptor that can lead to proliferation through growth factor binding and is known to induce angiogenesis in endothelial cells when bound to growth factors [53]. The increased MSC VEGF secretion induced by minocycline may have contributed an autocrine effect on the increased TEK expressed receptors that could lead to increased proliferation of MSCs after culture with minocycline, as the receptor responds to growth factor binding to induce downstream signaling that can lead to proliferation [53]. Due to the minocycline-induced increased expression of LGALS1 , we investigated the attachment of MSCs to ECM proteins in the presence of antibiotics.…”

Section: Discussionmentioning

confidence: 99%

Minocycline enhances the mesenchymal stromal/stem cell pro-healing phenotype in triple antimicrobial-loaded hydrogels

et al. 2017

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Mesenchymal stromal/stem cells (MSCs) have demonstrated pro-healing properties including an anti-inflammatory cytokine profile and the promotion of angiogenesis via expression of growth factors in pre-clinical models. MSCs encapsulated in poly(ethylene glycol) diacrylate (PEGdA) and thiolated gelatin poly(ethylene glycol) (Gel-PEG-Cys) crosslinked hydrogels have led to controlled cellular presentation at wound sites with favorable wound healing outcomes. However, the therapeutic potential of MSC-loaded hydrogels may be limited by non-specific protein adsorption on the delivery matrix that could facilitate the initial adhesion of microorganisms and subsequent virulent biofilm formation. Antimicrobials loaded concurrently in the hydrogels with MSCs could reduce microbial bioburden and promote healing, but the antimicrobial effect on the MSC wound healing capacity and the antibacterial efficacy of the hydrogels is unknown. We demonstrate that minocycline specifically induces a favorable change in MSC migration capacity, proliferation, gene expression, extracellular matrix (ECM) attachment, and adhesion molecule and growth factor release with subsequent increased angiogenesis. We then demonstrate that hydrogels loaded with MSCs, minocycline, vancomycin, and linezolid can significantly decrease bacterial bioburden. Our study suggests that minocycline can serve as a dual mechanism for the regenerative capacity of MSCs and the reduction of bioburden in triple antimicrobial-loaded hydrogels.

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“…1c). GeneAnalytics Pathway Analysis of differentially expressed genes revealed numerous pathways associated with aging (Supplemental Table 1), including gene pathways associated with cell adhesion, immune cell activation, stress response and vascular remodeling [18][19][20][21] linking them to inflammation, leukocyte adhesion, BBB maintanence and inhibition of cell proliferation. Analysis of the highly expressed and differentially expressed transcripts revealed an inflammatory and activated profile with age as illustrated by the doubling in mRNA expression of the MHC class I molecules β2microglobulin (B2m) and H2-K1, two of the most highly expressed transcripts in BECs (Fig.…”

Section: Aged Becs Are Transcriptionally Activatedmentioning

confidence: 99%

Aged blood inhibits hippocampal neurogenesis and activates microglia through VCAM1 at the blood-brain barrier

Yousef

Lee

et al. 2018

Preprint

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An aged circulatory environment can promote brain dysfunction and we hypothesized that the blood-brain barrier (BBB) mediates at least some of these effects. We observe brain endothelial cells (BECs) in the aged mouse hippocampus express an inflammatory transcriptional profile with focal upregulation of Vascular Cell Adhesion Molecule 1 (VCAM1), a protein that facilitates vascular-immune cell interactions. Concomitantly, the shed, soluble form of VCAM1 is prominently increased in the aged circulation of humans and mice, and aged plasma is sufficient to increase VCAM1 expression in cultured BECs and young mouse hippocampi. Systemic anti-VCAM1 antibody or genetic ablation of VCAM1 in BECs counteracts the detrimental effects of aged plasma on young brains and reverses aging aspects in old mouse brains. Thus, VCAM1 is a negative regulator of adult neurogenesis and inducer of microglial reactivity, establishing VCAM1 and the luminal side of the BBB as possible targets to treat age-related neurodegeneration.Brain structure and function deteriorate with age, steadily driving cognitive impairments and susceptibility to neurodegenerative disorders in humans 1 . How aging leads to these manifestations is poorly understood but two cellular hallmarks of brain aging are particularly noticeable. The first is an increase in activation of innate immune pathways and an increase in the activation state of microglia and astrocytes, frequently referred to as "neuroinflammation" 2-4 . The second aging hallmark is the precipitous loss of stem cell numbers and activity in the dentate gyrus (DG) of the hippocampus, one of two neurogenic regions of the adult mammalian brain 5 . The hippocampus is crucial for learning and memory, and is particularly vulnerable to age-related neurodegeneration and diseases such as Alzheimer's disease (AD) 6 . Hippocampal neurogenesis is important for some aspects of learning and memory, especially as it relates to spatial navigation and pattern separation 7 .While many of these age-related changes in the brain may be the consequences of cellintrinsic and brain-localized mechanisms of aging, we asked if changes in secreted signaling proteins, dubbed the communicome 8 , could be used to understand, characterize, and quantify aspects of brain aging and cognitive impairment. Indeed, such changes in plasma or CSF proteomes are not only abundant with aging and disease 9,10 , but factors in young blood or

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Signaling Network Map of Endothelial TEK Tyrosine Kinase

Cited by 30 publications

References 45 publications

Aberrant Endometrial DNA Methylome and Associated Gene Expression in Women with Endometriosis

Aberrant Endometrial DNA Methylome and Associated Gene Expression in Women with Endometriosis

Minocycline enhances the mesenchymal stromal/stem cell pro-healing phenotype in triple antimicrobial-loaded hydrogels

Aged blood inhibits hippocampal neurogenesis and activates microglia through VCAM1 at the blood-brain barrier

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