PubMed · 14883900
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X VILANOVA. 1951-09-26. [Nodular vasculitis].. https://pubmed.ncbi.nlm.nih.gov/14883900/
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It is widely assumed that subdural and retinal haemorrhage in infants can only result from traumatic rupture of vulnerable blood vessels. An alternative aetiology, that of vascular rupture resulting from excessive intraluminal pressure, is presented in three disease conditions. (1) Perlman et al., studying premature neonates requiring mechanical ventilation for respiratory distress syndrome, observed "cough-like" fluctuations in oesophageal pressure greater than 18 cms H2O, whose timing matched fluctuations in anterior cerebral artery flow. When 14 out of 24 neonates were paralysed (to prevent abdominal muscle activity) intraventricular haemorrhage developed in all 10 controls but in only one of the paralysed group during paralysis. (2) New analysis of pressure data extracted from a previous study of prolonged expiratory apnoea showed alveolar collapse induced 100 mmHg intrathoracic cough pressure surges. Superior vena cava pressures up to 50 mmHg were implied, and radial artery systolic pressures over 180 mmHg recorded. (3) Bordetella pertussis bacteria attach to cilia in the airways, but do not invade the underlying tissue. The irritation causes the powerful coughing paroxysms of whooping cough. Brain haemorrhages and retinal detachment have been observed to result from the high intravascular pressures produced. The data suggest that any source of intense airway irritation not easily removed (laryngeal infection, inhalation of regurgitated feed, fluff, smoke etc.) could induce similar bleeding, a paroxysmal cough injury (PCI). Additional objective evidence of inflicted trauma is necessary to distinguish between 'shaken baby syndrome' and PCI.
Although intravasation may be a critical rate-limiting step in the metastatic cascade, the role of oxidative stress in intravasation is unknown. We tested the hypothesis that reactive oxygen species (ROS), regulated by thioredoxin interacting protein (Txnip) through the action of thioredoxin (Trx), influence human SK-MEL-28 melanoma cell reverse (basolateral-to-apical) transendothelial migration (TEM) in vitro as a model for intravasation. Reverse transendothelial migration was dose-dependently induced by hydrogen peroxide 2.4-fold for 0.1 microM (P < 0.01) and 3.9-fold for 1 microM (P < 0.001) vs. control, and this effect was blocked by the antioxidant N-acetylcysteine. Overexpression of Txnip by infecting melanoma cells with adenovirus increased TEM 3-fold vs. control (P < 0.001), and this increase was blocked by N-acetylcysteine, indicating a redox-sensitive mechanism. Conversely, thioredoxin overexpression blocked hydrogen peroxide-induced TEM. Exposure to ultraviolet-A radiation increased ROS 1.8-fold (P < 0.01), and this was accompanied by a 45% reduction (P < 0.05) in thioredoxin activity and an 11.4-fold (P < 0.001) increase in Txnip gene expression. These data suggest that TEM of melanoma cells during intravasation is in part mediated by ROS-sensitive cellular signaling cascades, may be controlled by Txnip and its interaction with thioredoxin that in turn modulates cellular levels of oxidative stress, and may be initiated by ultraviolet-A induction of this cascade.
The molecular signature that defines tumor microvasculature will likely provide clues as to how vascular-dependent tumor proliferation is regulated. Using purified endothelial cells, we generated a database of gene expression changes accompanying vascular proliferation in invasive breast cancer. In contrast to normal mammary vasculature, invasive breast cancer vasculature expresses extracellular matrix and surface proteins characteristic of proliferating and migrating endothelial cells. We define and validate the up-regulated expression of VE-cadherin and osteonectin in breast tumor vasculature. In contrast to other tumor types, invasive breast cancer vasculature induced a high expression level of specific transcription factors, including SNAIL1 and HEYL, that may drive gene expression changes necessary for breast tumor neovascularization. We demonstrate the expression of HEYL in tumor endothelial cells and additionally establish the ability of HEYL to both induce proliferation and attenuate programmed cell death of primary endothelial cells in vitro. We also establish that an additional intracellular protein and previously defined metastasis-associated gene, PRL3, appears to be expressed predominately in the vasculature of invasive breast cancers and is able to enhance the migration of endothelial cells in vitro. Together, our results provide unique insights into vascular regulation in breast tumors and suggest specific roles for genes in driving tumor angiogenesis.