scholarly journals mTORC1-Mediated Angiogenesis is Required for the Development of Rosacea

2021 ◽  
Vol 9 ◽  
Author(s):  
Qinqin Peng ◽  
Ke Sha ◽  
Yingzi Liu ◽  
Mengting Chen ◽  
San Xu ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Mouse Model ◽  
Skin Lesions ◽  
Tube Formation ◽  
Human Endothelial Cells ◽  
Lesional Skin ◽  
Mtorc1 Signaling ◽  
Inhibition Of Angiogenesis

Although multiple evidences suggest that angiogenesis is associated with the pathophysiology of rosacea, its role is still in debate. Here, we showed that angiogenesis was enhanced in skin lesions of both rosacea patients and LL37-induced rosacea-like mice. Inhibition of angiogenesis alleviated LL37-induced rosacea-like features in mice. Mechanistically, we showed that mTORC1 was activated in the endothelial cells of the lesional skin from rosacea patients and LL37-induced rosacea-like mouse model. Inhibition of mTORC1 decreased angiogenesis and blocked the development of rosacea in mice. On the contrary, hyperactivation of mTORC1 increased angiogenesis and exacerbated rosacea-like phenotypes. Our in vitro results further demonstrated that inhibition of mTORC1 signaling significantly declined LL37-induced tube formation of human endothelial cells. Taken together, our findings revealed that mTORC1-mediated angiogenesis responding to LL37 might be essential for the development of rosacea and targeting angiogenesis might be a novel potential therapy.

scholarly journals Toxic Damage Increases Angiogenesis and Metastasis in Fibrotic Livers via PECAM-1

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Esther Raskopf ◽  
Maria Angeles Gonzalez Carmona ◽  
Christina Jay Van Cayzeele ◽  
Christian Strassburg ◽  
Tilman Sauerbruch ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Liver Damage ◽  
Tube Formation ◽  
Ethanol Exposure ◽  
Human Endothelial Cells ◽  
Cell Functions ◽  
Promising Tool ◽  
Toxic Damage

Excessive ethanol consumption is one of the main causes of liver fibrosis. However, direct effects of ethanol exposure on endothelial cells and their contribution to fibrogenesis and metastasis were not investigated. Therefore we analysed whether ethanol directly affects endothelial cells and if this plays a role during fibrogenesis and metastasis in the liver. Murine and human endothelial cells were exposed to ethanol for up to 72 hours.In vitro, effects on VEGF, HIF-1alpha, PECAM-1, and endothelial cell functions were analysed.In vivo, effects of continuous liver damage on blood vessel formation and metastasis were analysed by PECAM-1 immunohistochemistry. Ethanol increased HIF-1alpha and VEGF levels in murine and human endothelial cells. This resulted in enhanced intracellular signal transduction, and PECAM-1 expression as well as tube formation and wound healing.In vivo, toxic liver damage increased angiogenesis during fibrogenesis. Metastasis was also enhanced in fibrotic livers and located to PECAM-1 positive blood vessels compared to nonfibrotic mice. In conclusion, ethanol had strong effects on endothelial cells, which—at least in part—led to a profibrotic and prometastatic environment mediated by PECAM-1. Blockade of increased PECAM-1 expression could be a promising tool to inhibit fibrogenesis and metastasis in the liver.

Hydroxysafflor yellow A promotes angiogenesis in rat brain microvascular endothelial cells injured by oxygen-glucose deprivation/reoxygenation(OGD/R) through SIRT1-HIF-1α-VEGFA signaling pathway

2021 ◽  
Vol 18 ◽  
Author(s):  
Juxuan Ruan ◽  
Lei Wang ◽  
Jiheng Dai ◽  
Jing Li ◽  
Ning Wang ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Growth Factor ◽  
Signaling Pathway ◽  
Ischemia Reperfusion ◽  
Tube Formation ◽  
Microvascular Endothelial Cells ◽  
Brain Microvascular Endothelial Cells ◽  
Hydroxysafflor Yellow A ◽  
Microvascular Endothelial

Objective: Angiogenesis led by brain microvascular endothelial cells (BMECs) contributes to the remission of brain injury after brain ischemia reperfusion. In this study, we investigated the effects of hydroxysafflor yellow A(HSYA) on angiogenesis of BMECs injured by OGD/R via SIRT1-HIF-1α-VEGFA signaling pathway. Methods: The OGD/R model of BMECs was established in vitro by OGD for 2h and reoxygenation for 24h. At first, the concentrations of vascular endothelial growth factor (VEGF), Angiopoietin (ang) and platelet-derived growth factor (PDGF) in supernatant were detected by ELISA, and the proteins expression of VEGFA, Ang-2 and PDGFB in BMECs were tested by western blot; the proliferation, adhesion, migration (scratch healing and transwell) and tube formation experiment of BMECs; the expression of CD31 and CD34 were tested by immunofluorescence staining. The levels of sirtuin1(SIRT1), hypoxia-inducible factor-1α (HIF-1α), VEGFA mRNA and protein were tested. Results: HSYA up-regulated the levels of VEGF, Ang and PDGF in the supernatant of BMECs under OGD/R, and the protein expression of VEGFA, Ang-2 and PDGFB were increased; HSYA could significantly alleviate the decrease of cell proliferation, adhesion, migration and tube formation ability of BMECs during OGD/R; HSYA enhanced the fluorescence intensity of CD31 and CD34 of BMECs during OGD/R; HSYA remarkably up-regulated the expression of SIRT1, HIF-1α, VEGFA mRNA and protein after OGD/R, and these increase decreased after SIRT1 was inhibited. Conclusion: SIRT1-HIF-1α-VEGFA signaling pathway is involved in HSYA improves angiogenesis of BMECs injured by OGD/R.

Abstract P313: Over-expression Of Serine Threonine Kinase 35 Improves Cardiac Function In Streptozotocin Induced Diabetic Mice

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Darukeshwara Joladarashi ◽  
Yanana Zhu ◽  
Maria Cimini ◽  
Rajarajan Thandavarayan ◽  
Keith Youker ◽  
...  
Keyword(s):  
Mouse Model ◽  
Cardiac Function ◽  
Diabetic Control ◽  
Tube Formation ◽  
Cellular Functions ◽  
Serine Threonine Kinase ◽  
Angiogenic Proteins ◽  
Patients With Diabetes ◽  
Beneficial Action

Diabetic cardiomyopathy is a common complication in patients with diabetes and is associatedwith impaired responsiveness of ischemic myocardium to proangiogenic factors, subsequentlyleading to heart failure. STK35, a novel kinase that binds to nuclear actin, has been shown toregulate important cellular functions such as cell migration, proliferation, survival, andangiogenesis. Currently, the contribution of altered STK35 expression in human diseases remainsunexplored. In initial studies, we observed that human cardiac biopsies from diabetic patientsshowed a significant decrease in STK35 expression as compared to non-diabetic control hearts.Intriguingly, in a STZ-induced mouse model of diabetes, i.v . injection of rAAV9-STK35 to expressconstitutive STK35 in heart in FVB/N male mice promoted neovascularization and lowered cardiacfibrosis, leading to improved cardiac function of diabetic heart. Our in vitro studies observed highglucose decreased STK35 expression in mouse cardiac endothelial cells (MCEC), whereasSTK35 overexpression increased MCEC migration and vascular tube formation, and upregulatedMCEC to expression of multiple pro-angiogenic proteins. Taken together, our results demonstratethat cardiac-targeted STK35 gene therapy exerts a marked beneficial action by attenuating bothcardiac remodeling and cardiac function in a mouse model of diabetes mellitus. Mechanistically,the beneficial effect may be attributed, at least partially, to enhanced neovascularization in heart.

Vascular repair utilising immobilised heparin conjugate for protection against early activation of inflammation and coagulation

2015 ◽  
Vol 113 (06) ◽  
pp. 1312-1322 ◽  
Author(s):  
Sofia Nordling ◽  
Jaan Hong ◽  
Karin Fromell ◽  
Fredrik Edin ◽  
Johan Brännström ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Thrombus Formation ◽  
Innate Immune ◽  
Human Endothelial Cells ◽  
Coagulation Activation ◽  
Ischaemia Reperfusion Injury ◽  
Novel Approach ◽  
One Step ◽  
Chamber Model

SummaryIschaemia-reperfusion injury (IRI) poses a major challenge in many thrombotic conditions and in whole organ transplantation. Activation of the endothelial cells and shedding of the protective vascular glycocalyx during IRI increase the risk of innate immune activation, cell infiltration and severe thrombus formation, promoting damage to the tissue. Here, we present a novel one-step strategy to protect the vasculature by immobilisation of a unique multi-arm heparin conjugate to the endothelium. Applying a new in vitro blood endothelial cell chamber model, the heparin conjugate was found to bind not only to primary human endothelial cells but also directly to the collagen to which the cells adhered. Incubation of hypoxic endothelial cells with freshly drawn human blood in the blood chambers elicited coagulation activation reflected by thrombin anti-thrombin formation and binding of platelets and neutrophils. Immobilisation of the heparin conjugate to the hypoxic endothelial cells created a protective coating, leading to a significant reduction of the recruitment of blood cells and coagulation activation compared to untreated hypoxic endothelial cells. This novel approach of immobilising multi-arm heparin conjugates on the endothelial cells and collagen of the basement membrane ensures to protect the endothelium against IRI in thrombotic disorders and in transplantation.

scholarly journals An acute bleomycin inflammatory and fibrotic mouse model of morphea is dependent upon CXCL9 and CXCR3

2019 ◽  
Author(s):  
Jillian M. Richmond ◽  
Dhrumil Patel ◽  
Tomoya Watanabe ◽  
Colton J. Garelli ◽  
Madhuri Garg ◽  
...  
Keyword(s):  
Mouse Model ◽  
Localized Scleroderma ◽  
Lesional Skin ◽  
Chemokine Expression ◽  
Inflammatory Phase ◽  
Deficient Mice ◽  
Over Time ◽  
Cutaneous Fibrosis

AbstractMorphea, or localized scleroderma, is characterized by an inflammatory phase followed by cutaneous fibrosis, which may lead to disfigurement and/or disability. Previous work from our group showed that the CXCR3 ligands CXCL9 and CXCL10 are highly upregulated in lesional skin of morphea patients. Here, we used an acute inflammatory and fibrotic bleomycin mouse model of morphea to examine the role of the CXCR3 chemokine axis in pathogenesis. We first characterized which cells produce the CXCR3 ligands in the skin using the Reporter of Expression of CXCR3 ligands mouse (REX3). We found that fibroblasts contribute the bulk of CXCL9 and CXCL10, whereas endothelial cells are key dual chemokine producers. Macrophages, which have high MFI of chemokine expression, upregulated CXCL9 production over time, fibroblasts CXCL10 production, and T cells dual chemokine expression. To determine whether bleomycin treatment could directly induce expression of these chemokines, we treated cultured REX3 mouse dermis monolayers in vitro with bleomycin or IFNγ with TNF and found that bleomycin could induce low amounts of CXCL9 directly in fibroblasts, whereas the cytokines were required for optimal CXCL9 and CXCL10 production. To determine whether these chemokines are mechanistically involved in pathogenesis, we induced fibrosis in CXCL9, CXCL10, or CXCR3 deficient mice and found that fibrosis is dependent on CXCL9 and CXCR3. Addition of recombinant CXCL9, but not CXCL10, to cultured mouse fibroblasts induces collagen 1a1 mRNA expression, indicating the chemokine itself can contribute to fibrosis. Taken together, our studies provide evidence that acute intradermal bleomycin administration in mice can model inflammatory morphea, and that CXCL9 and its receptor CXCR3 are mechanistically involved in pathogenesis.One Sentence SummaryCXCL9 drives acute morphea pathogenesis in mice.

Centrifugal enhancement of Kaposi's sarcoma-associated virus infection of human endothelial cells in vitro

2008 ◽  
Vol 154 (1-2) ◽  
pp. 160-166 ◽  
Author(s):  
Seung-Min Yoo ◽  
Ae-Kyung Ahn ◽  
Taegun Seo ◽  
Hyo Bong Hong ◽  
Myung-Ae Chung ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Virus Infection ◽  
Kaposi's Sarcoma ◽  
Kaposi’S Sarcoma ◽  
Human Endothelial Cells
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