Browsing by Subject "ENDOTHELIUM"

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  • McGarvey, Alison C.; Rybtsov, Stanislav; Souilhol, Celine; Tamagno, Sara; Rice, Ritva; Hills, David; Godwin, Duncan; Rice, David; Tomlinson, Simon R.; Medvinsky, Alexander (2017)
    In the developing embryo, hematopoietic stem cells (HSCs) emerge from the aorta-gonad-mesonephros (AGM) region, but the molecular regulation of this process is poorly understood. Recently, the progression from E9.5 to E10.5 and polarity along the dorso-ventral axis have been identified as clear demarcations of the supportive HSC niche. To identify novel secreted regulators of HSC maturation, we performed RNA sequencing over these spatiotemporal transitions in the AGM region and supportive OP9 cell line. Screening several proteins through an ex vivo reaggregate culture system, we identify BMP ER as a novel positive regulator of HSC development. We demonstrate that BMP ER is associated with BMP signaling inhibition, but is transcriptionally induced by BMP4, suggesting that BMP ER contributes to the precise control of BMP activity within the AGM region, enabling the maturation of HSCs within a BMP-negative environment. These findings and the availability of our transcriptional data through an accessible interface should provide insight into the maintenance and potential derivation of HSCs in culture.
  • Pesonen, Eero; Passov, Arie; Salminen, Ulla-Stina; Ilmakunnas, Minna; Vento, Antti; Aittomäki, Juha; Andersson, Sture; Schramko, Alexey (2019)
    Background. Heparin binding protein (HBP) is released from neutrophilic secretory vesicles upon neutrophil adhesion on the endothelium. HBP mediates capillary hyperpermeability experimentally. In sepsis, HBP predicts organ dysfunction. Cardiopulmonary bypass induces neutrophil activation and hyperpermeability. We hypothesized that in cardiopulmonary bypass, HBP is released in the reperfused coronary circulation concomitantly with neutrophil adhesion. Methods. In 30 patients undergoing aortic valve replacement, concomitant blood samples were drawn from the coronary sinus and arterial line before aortic cross-clamping and 5 minutes after reperfusion to calculate transcoronary differences. Plasma HBP concentrations, neutrophil markers lactoferrin and myeloperoxidase, myocardial injury marker heart-type fatty acid binding protein, and leukocyte differential counts were measured. Results. Arterial HBP was 4.1 ng/mL (interquartile range [IQR], 3.6 to 5.3 ng/mL) preoperatively and 150.0 ng/mL (IQR, 108.2 to 188.6 ng/mL) after aortic declamping. HBP increased 39-fold, lactoferrin 16-fold, and myeloperoxidase fourfold during cardiopulmonary bypass. Before cardiopulmonary bypass, there were marginal transcoronary differences in HBP (1.4 ng/mL; IQR, -0.4 to 3.6 ng/mL; p = 0.001) and heart-type fatty acid binding protein (0.4 ng/mL; IQR, -0.04 to 3.5 ng/mL; p = 0.001) but not in the other indicators. During reperfusion, transcoronary HBP release (6.4 ng/mL; IQR, 1.8 to 13.7; ng/mL; p <0.001) was observed concomitantly with transcoronary neutrophil sequestration (-0.14 3 109/L; IQR, -0.28 to 0.01 3 109/L; p = 0.001) and transcoronary heart-type fatty acid binding protein release (6.9 ng/mL; IQR, 3.0 to 25.8 ng/mL; p <0.001). There were no transcoronary differences in lactoferrin or myeloperoxidase during reperfusion. Conclusions. Cardiopulmonary bypass results in substantial increase in circulating HBP. HBP is also released from the reperfused coronary circulation concomitantly with coronary neutrophil adhesion and myocardial injury. HBP may be one candidate for a humoral factor mediating capillary leak in cardiopulmonary bypass. (C) 2019 by The Society of Thoracic Surgeons
  • Salmenkari, Hanne; Issakainen, Tomi; Vapaatalo, Heikki; Korpela, Riitta (2015)
    AIM: To investigate local corticosterone production and angiotensin- I converting enzyme (ACE) protein expression and their interaction in healthy and inflamed intestine. METHODS: Acute intestinal inflammation was induced to six weeks old male Balb/c mice by administration of either 3% or 5% dextran sodium sulfate (DSS) in drinking water for 7 d (n = 12 in each group). Healthy controls (n = 12) were given tap water. Corticosterone production and ACE protein shedding were measured from ex vivo incubates of the small and large intestine using EIA and ELISA, respectively. Morphological changes of the intestinal wall were assessed in hematoxylin-eosin stained tissue preparations of jejunum and distal colon. Effects of angiotensin II, captopril and metyrapone on corticosterone production was assessed by incubating pieces of small intestine of healthy mice in the presence of 0.1, 1 or 10 mu mol/L angiotensin II, 1, 10 or 100 mu mol/L captopril or 1, 10 or 100 mu mol/L metyrapone solutions and measuring corticosterone released to the incubation buffer after 90 min (n = 5 in each group). RESULTS: Both concentrations of DSS induced inflammation and morphological changes in large intestines but not in small intestines. Changes were observed as distortions of the crypt structure, mucosal erosion, immune cell infiltration to the mucosa and submucosal edema. Ex vivo corticosterone production (2.9 +/- 1.0 ng/mL vs 2.0 +/- 0.8 ng/mL, P = 0.034) and ACE shedding (269.2 +/- 97.1 ng/mL vs 175.7 +/- 52.2 ng/mL, P = 0.016) were increased in small intestines in 3% DSS group compared to the controls. In large intestine, corticosterone production was increased compared to the controls in both 3% DSS (229 +/- 81 pg/mL vs 158 +/- 30 pg/mL, P = 0.017) and 5% DSS groups (366 +/- 163 pg/mL vs 158 +/- 30 pg/mL, P = 0.002). Large intestine ACE shedding was increased in 5% DSS group (41.5 +/- 9.0 ng/mL vs 20.9 +/- 5.2 ng/mL, P = 0.034). Angiotensin II treatment augmented corticosterone production in small intestine at concentration of 10 mu mol/L (0.97 +/- 0.21 ng/mg protein vs 0.40 +/- 0.09 ng/mg protein, P = 0.036). CONCLUSION: Intestinal ACE shedding is increased by DSS-induced intestinal inflammation and parallels local corticosterone production. ACE product angiotensin. stimulates corticosterone formation in healthy intestine.