A novel extracellular role for tissue transglutaminase in matrix-bound VEGF-mediated angiogenesis.

The importance of tissue transglutaminase (TG2) in angiogenesis is unclear and contradictory. Here we show that inhibition of extracellular TG2 protein crosslinking or downregulation of TG2 expression leads to inhibition of angiogenesis in cell culture, the aorta ring assay and in vivo models. In a human umbilical vein endothelial cell (HUVEC) co-culture model, inhibition of extracellular TG2 activity can halt the progression of angiogenesis, even when introduced after tubule formation has commenced and after addition of excess vascular endothelial growth factor (VEGF). In both cases, this leads to a significant reduction in tubule branching. Knockdown of TG2 by short hairpin (shRNA) results in inhibition of HUVEC migration and tubule formation, which can be restored by add back of wt TG2, but not by the transamidation-defective but GTP-binding mutant W241A. TG2 inhibition results in inhibition of fibronectin deposition in HUVEC monocultures with a parallel reduction in matrix-bound VEGFA, leading to a reduction in phosphorylated VEGF receptor 2 (VEGFR2) at Tyr¹²¹4 and its downstream effectors Akt and ERK1/2, and importantly its association with ß1 integrin. We propose a mechanism for the involvement of matrix-bound VEGFA in angiogenesis that is dependent on extracellular TG2-related activity.

White adipose tissue production and release of IL-6 and TNF-alpha do not parallel circulating and cerebrospinal fluid concentrations in pregnant rats.

IL-6 and TNF-alpha are synthesized in white adipose tissue both by adipocytes and by the stroma-vascular fraction. They both are known to interfere with insulin signaling, reducing insulin sensitivity and lipid deposition. At a central level, IL-6 enhances sympathetic nervous system activity, thus enhancing lipolysis and reducing fat mass. During late pregnancy, white adipose tissue (WAT) mass increases and insulin sensitivity decreases. To assess the involvement of both adipokines in such processes, we analyzed the tissue content and release of both adipokines in parametrial and subcutaneous WAT depots and their circulating and cerebrospinal fluid concentrations in nonpregnant rats and in pregnant rats by days 8, 15, and 19 of pregnancy. The tissue content of both adipokines was enhanced 5-6 times by day 8 until the end of pregnancy in parametrial WAT, whereas the increase took place by day 15-19 in subcutaneous WAT. No increase in tissue release was detected, suggesting a local action. However, circulating IL-6 concentration was enhanced by day 8 until the end of pregnancy, suggesting sources other than WAT. IL-6 concentration in cerebrospinal fluid paralleled the increases in serum by days 8 and 15, suggesting a systemic origin. However, it returned to basal levels by day 19, suggesting a central control for IL-6 entrance. TNF-alpha was not detected in either serum or cerebrospinal fluid. These results led us to conclude that across pregnancy adipokines control WAT depots in a time- and depot-dependent manner. They do so directly, by local production, but the enhanced concentrations of both circulating and CSF IL-6 suggest an indirect action mediated by the nervous system.

Lesión quística mediastínica de histología indeterminada / Mediastinal cystic lesion of unknown histology

Los quistes mediastínicos son malformaciones benignas de origen congénito que representan el 20% del total de lesiones primarias del mediastino. Se clasifican según el tipo celular de revestimiento epitelial que contienen. En un 20% de los casos, debido a procesos infecciosos y/o hemorrágicos, se produce una desestructuración del epitelio originario, y es enestos casos cuando los denominamos quistes de histología indeterminada o inespecífica. Aunque existe una amplia variedad, tanto en histología como en localización, cuando presentan clínica lo hacen de forma similar. El dolor torácico es el síntoma más frecuente seguido de la tos, la disnea y la disfagia. Presentamos el caso de un varón de 45 años de edad que consultó por un dolor centrotorácico intenso de aparición brusca. La tomografía axial computarizada (TAC) y la resonanciamagnética (RM) evidenciaron una gran lesión quística que ocupaba el mediastino posterior. La ecoendoscopiaesofágica descartó el origen esofágico de la lesión. Se intervino el paciente mediante toracotomía posterolateral derecha y se realizó la exéresis de la lesión. El curso postoperatorio transcurrió sin complicaciones. El diagnóstico histopatológicoconcluyó que se trataba de una lesión quística de histología indeterminada

Mediastinal cysts are uncommon congenital and benign malformations that represent 20% of all primary mediastinal lesions. They are classified by their specific histologic features. 20% of mediastinal cysts lack specific histologic features, possibly because of haemorrhage or infection, and are termed indeterminate or non-specific cysts. Despite varied location and histology, clinical presentation of mediastinal cysts is similar. Chest pain is the most common symptom followed by cough, dyspnoea and dysphagia. We report the case of a 45-year-old man who sought medical attention for acute chest pain. Computed tomography and magnetic resonance showed a large cystic lesion in the posterior mediastinum. Endoscopic ultrasound excluded a communication of the cyst with the oesophagus. The tumor was resected through a right thoracotomy. No postsurgical complications occurred. The histopathological diagnosis was cystic lesion of nonspecific histology2

Control by reproduction-related hormones of resistin expression and plasma concentration.

Although not simultaneously, resistin expression in white adipose tissue (WAT) and resistin plasma concentration have been shown to increase in pregnant rats. To clarify the involvement of sex hormones in such increases, we administered for 3-5 days progesterone, estradiol, or human chorionic gonadotropin (hCG) to female rats in dioestrus II. Progesterone increased resistin expression retroperitoneal WAT but lacked effect in parametrial or subcutaneous depots. It also increased resistin plasma concentration. Estradiol decreased resistin expression in both parametrial and inguinal WAT but was without effect on retroperitoneal depots. It did not alter plasma resistin. Human hCG increased resistin expression in all the visceral depots examined - parametrial, inguinal and retroperitoneal - but did not change plasma resistin. These results show that hormonal influences in resistin expression are depot-dependent and can run separately from changes in its plasma concentration. Besides, the locally restricted effect of progesterone in resistin expression compared with that of hCG suggests it is not the only hormone enhancing resistin expression in early pregnancy. However, it could enhance resistin release in late pregnancy. Estradiol could be involved in the decrease of resistin expression in late pregnancy. Finally, since hCG acts through LH receptors, our results suggest that they are present in WAT and that they control resistin expression.

Adiponectin values are unchanged during pregnancy in rats.

Adiponectin is believed to be a key factor in determining insulin sensitivity. In turn, insulin sensitivity is known to change from an enhanced state in early pregnancy to a reduced one in late pregnancy. A role for adiponectin in these changes has been proposed for mice but questioned for humans. We addressed this issue in rats by measuring adiponectin expression in both visceral and subcutaneous white adipose tissue, together with tissue content and release of the hormone in non-pregnant and in pregnant rats by days 8, 15 and 19 of pregnancy. Plasma concentration was also determined. No differences were found in any of the parameters measured between non-pregnant and pregnant rats at any time of pregnancy despite changes in white adipose tissue mass and insulin sensitivity. Adiponectin was also detected in cerebrospinal fluid at a concentration 1,000 times lower than in plasma, but again no differences were found between non-pregnant and pregnant animals. It is concluded that adiponectin does not play any role in regulating changes in insulin sensitivity during pregnancy in rats.