Proinflammatory Cytokines Induce Hyaluronan Synthesis and Monocyte Adhesion in Human Endothelial Cells through Hyaluronan Synthase 2 (HAS2) and the Nuclear Factor-κB (NF-κB) Pathway

Vigetti, Davide; Genasetti, Anna; Karousou, Evgenia; Viola, Manuela; Moretto, Paola; Clerici, Moira; Deleonibus, Sara; Luca, Giancarlo De; Hascall, Vincent C.; Passi, Alberto

doi:10.1074/jbc.m110.134536

Cited by 114 publications

(111 citation statements)

References 40 publications

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“…Especially, HA is produced by both ECs and VSMCs, and its deposition creates a hygroscopic environment suitable for cell migration (16,17). In accordance with a previous study in human umbilical vein endothelial cells (HUVECs) (18), only HAS2 and HAS3 mRNA were detected in HPAECs. We showed that BMP9 and BMP10 specifically regulated HAS2 mRNA expression.…”

Section: Discussionsupporting

confidence: 65%

BMP9 and BMP10 are necessary for proper closure of the ductus arteriosus

Levet

Ouarné

Ciais

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The transition to pulmonary respiration after birth requires rapid alterations in the structure of the mammalian cardiovascular system. One dramatic change that occurs is the closure of the ductus arteriosus (DA), an arterial connection in the fetus that directs blood flow away from the pulmonary circulation. Two members of the TGFβ family, bone morphogenetic protein 9 (BMP9) and BMP10, have been recently involved in postnatal angiogenesis, both being necessary for remodeling of newly formed microvascular beds. The aim of the present work was to study whether BMP9 and BMP10 could be involved in closure of the DA. We found that Bmp9 knockout in mice led to an imperfect closure of the DA. Further, addition of a neutralizing anti-BMP10 antibody at postnatal day 1 (P1) and P3 in these pups exacerbated the remodeling defect and led to a reopening of the DA at P4. Transmission electron microscopy images and immunofluorescence stainings suggested that this effect could be due to a defect in intimal cell differentiation from endothelial to mesenchymal cells, associated with a lack of extracellular matrix deposition within the center of the DA. This result was supported by the identification of the regulation by BMP9 and BMP10 of several genes known to be involved in this process. The involvement of these BMPs was further supported by human genomic data because we could define a critical region in chromosome 2 encoding eight genes including BMP10 that correlated with the presence of a patent DA. Together, these data establish roles for BMP9 and BMP10 in DA closure.T he ductus arteriosus (DA) is a large blood vessel whose obstruction is essential for the transition from fetal to neonatal circulation. It is a fetal arterial shunt connecting the pulmonary artery with the aortic arch. During fetal life, the DA directs deoxygenated blood away from the pulmonary circulation and toward the descending aorta, bypassing the nonventilated fetal lungs. After birth, the DA closes spontaneously within 1-3 h in small rodents or within 24-48 h in human newborns (1, 2). Although an open DA is required for fetal survival, the persistence of a patent DA (PDA) after birth is a major cause of morbidity and mortality, particularly in preterm neonates, leading to severe complications, including pulmonary hypertension, right ventricular dysfunction, postnatal infections, and respiratory failure. The incidence of PDA has been estimated to be one in 500 interm newborns and accounts for the majority of all cases of congenital heart disease in preterm newborns. It is currently believed that DA closure involves a two-step process (3, 4). The first, provisional closure, also called functional closure, occurs at birth and is accomplished by smooth muscle cell contraction and DA constriction. The second step, named anatomical closure, involves a profound remodeling of cells within the former DA lumen and permits permanent closure of the DA. Although several factors have been implicated in DA closure (oxygen tension, prostaglandin E2, laminin, growth ho...

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Section: Discussionsupporting

confidence: 65%

BMP9 and BMP10 are necessary for proper closure of the ductus arteriosus

Levet

Ouarné

Ciais

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Increased concentrations of HA indicate that its metabolism is altered in cancer cells, and the imbalance of HA synthesis and/or degradation may play an important role in tumor progression (33). HAS2 mainly produces high molecular weight HA (200-2000 kDa) and it is involved in a variety of both pathological and physiological activities, including proliferation, differentiation, inflammation, epithelial to mesenchymal transition (EMT) and cancer progression (38)(39)(40). Furthermore, it was recently reported that HAS2 plays an important prometastatic role by generating a favorable microenvironment of cancer stem-like cells (41).…”

Section: Discussionmentioning

confidence: 99%

4-Methylumbelliferone leads to growth arrest and apoptosis in canine mammary tumor cells

et al. 2012

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Abstract. Hyaluronan (HA), a major component of the extracellular matrix (ECM), is synthesized by HA synthase (HAS) 1, HAS2 and HAS3 and is intricately involved in cell growth and metastasis. The HA synthesis inhibitor 4-methylumbelliferone (4-MU) has been reported to exhibit anticancer properties in various types of malignant tumors. However, the underlying mechanisms at the molecular and cellular levels remain unclear. In this study, to establish an animal model for studying the function of HA in human breast cancer, we investigated the antitumor effects of 4-MU using canine mammary tumor (CF33) cells. First, we investigated the effects of 4-MU on HA production in CF33 cells. Quantitative analysis of HA in culture media showed that 4-MU inhibited HA synthesis, accompanied by downregulation of HAS2 mRNA levels, in a dose-dependent manner at 24-72 h. Additionally, we observed a 4-MU-mediated decrease in the extent of the cell-associated HA matrix. We examined the effect of 4-MU on cell growth and apoptosis in CF33 cells. 4-MU markedly inhibited cell proliferation and induced apoptosis in CF33 cells. In particular, our experiments showed that the mechanism of 4-MU-induced apoptosis in CF33 cells involved increased levels of expression of pro-apoptotic BAX mRNA and protein molecules. These data suggest that 4-MU may be a candidate therapeutic agent for the treatment of canine mammary tumors. Furthermore, this study provides the first indication that the canine mammary tumor may be a suitable model for comparative study of the function of HA in human breast cancer. IntroductionMammary tumors in dogs occur at a frequency of 3 times the incidence of mammary tumors in humans and have recorded a higher incidence rate than other livestock (1). Mammary tumors are the most frequent cutaneous neoplasms in female dogs, and approximately 50% are diagnosed as malignant tumors (2). Following surgical excision, approximately 48% of the affected dogs die or are euthanized within 1 year due to tumor recurrence or metastasis (3). Canine mammary tumors are heterogeneous, and the different clinical and biological features (4) make it difficult to determine a prognosis and treatment for affected dogs, as is often the case in humans. Additional and reliable tools for effective therapy are required in veterinary medicine. Furthermore, a recent study revealed clear evidence of a similarity between human and dog tumors in regard to the deregulation of several cancer-related genes, including PI3K/Akt, PTEN and Wnt-β catenin and MAPK signaling (5). Accordingly, canine mammary tumors can also provide a suitable natural model for the comparative study of human breast cancer (5-7).Hyaluronan (HA) is a non-sulfated linear glycosaminoglycan that consists of repeating disaccharide subunits of glucuronic acid and N-acetylglucosamine (8,9). It is ubiquitously distributed in the extra-and pericellular spaces of most animal tissues (8,9). HA plays a critical role in regulating matrix assembly, cell migration, differentiation and proliferation (9-11)...

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“…[29][30][31] In vitro studies have shown that inflammatory cytokines, particularly IL-1, IL-6, and TNF-a, as well as reactive oxygen species are involved in the degradation of HA. [32][33][34] High serum levels of HA have been reported in CKD [35][36][37] and seem to be a risk predictor of poor survival in dialysis. 38 However, the mechanisms underlying the increased levels have not been fully explained.…”

Section: Discussionmentioning

confidence: 99%

Damage of the Endothelial Glycocalyx in Dialysis Patients

Vlahu¹,

Lemkes²,

Struijk

et al. 2012

Journal of the American Society of Nephrology

233

229

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Damage to the endothelial glycocalyx, which helps maintain vascular homeostasis, heightens the sensitivity of the vasculature to atherogenic stimuli. Patients with renal failure have endothelial dysfunction and increased risk for cardiovascular morbidity and mortality, but the state of the endothelial glycocalyx in these patients is unknown. Here, we used Sidestream Darkfield imaging to detect changes in glycocalyx dimension in dialysis patients and healthy controls from in vivo recordings of the sublingual microcirculation. Dialysis patients had increased perfused boundary region and perfused diameters, consistent with deeper penetration of erythrocytes into glycocalyx, indicating a loss of glycocalyx barrier properties. These patients also had higher serum levels of the glycocalyx constituents hyaluronan and syndecan-1 and increased hyaluronidase activity, suggesting the shedding of these components. Loss of residual renal function had no influence on the imaging parameters but did associate with greater shedding of hyaluronan in blood. Furthermore, patients with higher levels of inflammation had more significant damage to the glycocalyx barrier. In conclusion, these data suggest that dialysis patients have an impaired glycocalyx barrier and shed its constituents into blood, likely contributing to the sustained endothelial cell activation observed in ESRD.

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Proinflammatory Cytokines Induce Hyaluronan Synthesis and Monocyte Adhesion in Human Endothelial Cells through Hyaluronan Synthase 2 (HAS2) and the Nuclear Factor-κB (NF-κB) Pathway

Cited by 114 publications

References 40 publications

BMP9 and BMP10 are necessary for proper closure of the ductus arteriosus

BMP9 and BMP10 are necessary for proper closure of the ductus arteriosus

4-Methylumbelliferone leads to growth arrest and apoptosis in canine mammary tumor cells

Damage of the Endothelial Glycocalyx in Dialysis Patients

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