Interface Properties of Circumventricular Organs in Salt and Fluid Balance.

The "sensory" circumventricular organs, with their leaky blood-brain barriers, permit contact between brain neurons and blood-borne molecules. Body fluid balance and cardiovascular control involve established interface functions of subfornical organs. Their recently identified target functions for hormones released during digestion suggest that they may coordinate fluid and food intake.

Arteriogenesis Versus Angiogenesis: Two Mechanisms of Vessel Growth.

After birth, new blood vessel formation proceeds via angiogenesis or arteriogenesis. Angiogenesis (capillary sprouting) results in higher capillary density. Arteriogenesis (rapid proliferation of collateral arteries) is potentially able to significantly alter the outcome of coronary and peripheral artery disease.

Nitric Oxide and Body Temperature Control.

Pharmacological studies of thermoregulatory effector and neuronal responses indicate that nitric oxide (NO) may have differential roles in the control of body temperature and during fever. Histochemical analysis of site-specific changes in NO synthase activity in defined states of thermal stimulation appears a promising approach to unravel the underlying hypothalamic neuronal cytoarchitecture.

Caspase-mediated cleavage of hematopoietic progenitor kinase 1 (HPK1) converts an activator of NFkappaB into an inhibitor of NFkappaB.

Hematopoietic progenitor kinase 1 (HPK1), a mammalian Ste20-related protein kinase, is a potent stimulator of the stress-activated protein kinases (SAPKs/JNKs). Here we report activation of NFkappaB transcription factors by HPK1 that was independent of SAPK/JNK activation. Overexpression of a dominant-negative SEK1 significantly inhibited SAPK/JNK activation, whereas NFkappaB stimulation by HPK1 remained unaffected.

Time course of arteriogenesis following femoral artery occlusion in the rabbit.

Objective: We examined the time course of arteriogenesis (collateral artery growth) after femoral artery ligation and the effect of monocyte chemoattractant protein-1 (MCP-1).

Methods: New Zealand White rabbits received MCP-1 or phosphate buffered saline (PBS) for a 1-week period, either directly or 3 weeks after femoral artery ligation (non-ischemic model). A control group was studied with intact femoral arteries and another 1 min after acute femoral artery ligation.

Stimulation of arteriogenesis; a new concept for the treatment of arterial occlusive disease.

After birth two forms of vessel growth can be observed; angiogenesis and arteriogenesis. Angiogenesis refers to the formation of capillary networks. Arteriogenesis refers to the growth of preexistent collateral arterioles leading to formation of large conductance arteries that are well capable to compensate for the loss of function of occluded arteries.

Vascular endothelial growth factor (VEGF) stimulates monocyte migration through endothelial monolayers via increased integrin expression.

Monocytes play an important role in collateral vessel formation (arteriogenesis) by attaching to activated endothelium and by invading the walls of innate collateral vessels where they produce growth factors. Previous studies have demonstrated that this process can be promoted by several chemokines and growth factors. In this study we examined the interaction between monocytes and endothelium under stimulation of the angiogenic agent vascular endothelial growth factor (VEGF).

Discontinuation of fucose therapy in LADII causes rapid loss of selectin ligands and rise of leukocyte counts.

Leukocyte adhesion deficiency type II (LADII) is a rare inherited disorder of fucose metabolism. Patients with LADII lack fucosylated glycoconjugates, including the carbohydrate ligands of the selectins, leading to an immunodeficiency caused by the lack of selectin-mediated leukocyte-endothelial interactions. A simple and effective therapy has recently been described for LADII, based on the administration of oral fucose.

Tumor endothelium-specific transgene expression directed by vascular endothelial growth factor receptor-2 (Flk-1) promoter/enhancer sequences.

The receptor tyrosine kinase Flk-1 plays a pivotal role in the development of the vascular system and in the vascularization of a wide variety of tumors. We have investigated the activity of cis-acting sequences of the murine Flk-1 gene in the tumor endothelium of experimental tumor models in vivo. B16 melanoma, BFS-1 fibrosarcoma, and polyoma middle T-induced mammary adenocarcinoma were grown in transgenic mice that express the LacZ reporter gene under the control of a 939-bp Flk-1 promoter fragment and an enhancer element located in a 2.

Role of SCL/Tal-1, GATA, and ets transcription factor binding sites for the regulation of flk-1 expression during murine vascular development.

The receptor tyrosine kinase Flk-1 is essential for embryonic blood vessel development and for tumor angiogenesis. To identify upstream transcriptional regulators of Flk-1, the gene regulatory elements that mediate endothelium-specific expression in mouse embryos were characterized. By mutational analysis, binding sites for SCL/Tal-1, GATA, and Ets transcription factors located in the Flk-1 enhancer were identified as critical elements for the endothelium-specific Flk-1 gene expression in transgenic mice.

Effect of astroglial cells on hypoxia-induced permeability in PBMEC cells.

An in vitro model of the blood-brain barrier (BBB), consisting of porcine brain-derived microvascular endothelial cells (PBMEC), was used to evaluate the effect of astrocytes in the BBB disruption during hypoxia. Hypoxia-induced hyperpermeability was decreased significantly in a coculture model of astroglia cells, either astrocytes or C6 glioma cells, with PBMEC and, to the same extent, when glia cell-conditioned medium was used. Corresponding to effects on hypoxia-induced hyperpermeability, astrocyte- and C6 cell-conditioned medium diminished hypoxia-induced vascular endothelial growth factor (VEGF) mRNA and protein expression, which recently was shown to be responsible for hypoxia-induced permeability changes in vitro.

Therapeutic angiogenesis for ischemic heart disease.

The de-novo formation of vessels (angiogenesis) and the remodelling of preexisting collateral vessels (arteriogenesis) are processes that occur naturally in ischemic heart disease. Promoting these processes by administration of various substances or other physical stimuli (therapeutic angiogenesis) may provide a future strategy for the treatment of ischemic vascular diseases. Mechanisms of angiogenesis and arteriogenesis, as well as trials of therapeutic angiogenesis in animal models and humans are reviewed.

Inhibition of the ER-kinase cascade by PD98059 and UO126 counteracts ischemic preconditioning in pig myocardium.

Our previous studies suggested a protective role of the extracellular signal-regulated kinases (ERKs) cascade in ischemic preconditioning (IP) in the porcine heart. To test this hypothesis further, we studied the influence of the novel specific inhibitors of mitogen-activated protein kinase kinases (MEK 1/2) PD98059 (PD) and UO126 (UO) in IP. The substances were infused intramyocardially and UO also systemically in anesthetized, ventilated, open-chested, male pigs.

Disruption of epithelial tight junctions is prevented by cyclic nucleotide-dependent protein kinase inhibitors.

Tight junctions (TJs), the most apical of the intercellular junctions, prevent the passage of ions and molecules through the paracellular pathway. Intracellular signalling molecules are likely to be involved in the regulation of TJ integrity. In order to specifically investigate the role of protein kinase A (PKA) in the maintenance of epithelial TJ integrity, calcium-switch experiments were performed, in which calcium was removed from EpH4 and MDCK culture medium, in the absence or presence of the PKA inhibitors H-89 or HA-1004.

Potassium channel openers and blockers in coronary artery disease. Comparison to betablockers and calcium antagonists.

Potassium channel openers and blockers, which belong to a novel class of vasodilator drugs and to the class of specific bradycardic substances, are potential new antianginal drugs. Experimental findings in vivo suggest that bimakalim is a new substance characterized as ATP-sensitive K+ channel openers, since it exerts preferential vasodilation of the collateral circulation of the coronary vasculature and both leads to increase blood flow to ischemic areas and to attenuate the ST segment elevation caused by regional ischemia in the canine heart. Opening of KATP increases the conductivity of potassium ions which results in hyperpolarization of smooth muscle membranes, thus producing vasodilation.

Photoendocrine signal transduction in pineal photoreceptors of the trout. Role of cGMP and nitric oxide.

This study describes the presence and distribution of cGMP-immunoreactivity and of the nitric oxide (NO) synthesizing enzyme, NO synthase (NOS), as demonstrated by use of the NADPH-diaphorase technique in directly light sensitive pineal organ of the trout. Cyclic GMP immunohistochemistry revealed immunoreactivity in pineal photoreceptor cells that were identified by double-labeling with S-antigen, whereas NADPH-positive structures were located adjacent to these photoreceptor cells. Since NO is known to stimulate synthesis of cGMP, these results indicate a role for NO in pineal function, e.

Astrocytes in sensory circumventricular organs of the rat brain express functional binding sites for endothelin.

Sensory circumventricular organs bordering the anterior third cerebral ventricle, the subfornical organ and the organum vasculosum laminae terminalis, lack blood-brain barrier characteristics and are therefore accessible to circulating peptides like endothelins. Astrocytes of the rat subfornical organ and organum vasculosum laminae terminalis additionally showed immunocytochemical localization of endothelin-1/endothelin-3-like peptides, possibly acting as circumventricular organ-intrinsic modulators. Employing [125I]endothelin-1 as radioligand, quantitative autoradiography demonstrated specific binding sites throughout the rat organum vasculosum laminae terminalis and subfornical organ, and competitive displacement studies revealed expression of both ET(A) and ET(B) receptor subtypes for either circumventricular organ.

A newly created splice donor site in exon 25 of the MyBP-C gene is responsible for inherited hypertrophic cardiomyopathy with incomplete disease penetrance.

Background: Hypertrophic cardiomyopathy is a myocardial disorder resulting from inherited sarcomeric dysfunction. We report a mutation in the myosin-binding protein-C (MyBP-C) gene, its clinical consequences in a large family, and myocardial tissue findings that may provide insight into the mechanism of disease.

Methods And Results: History and clinical status (examination, ECG, and echocardiography) were assessed in 49 members of a multigeneration family.

Inhibition of the cardiac p38-MAPK pathway by SB203580 delays ischemic cell death.

We report that SB203580 (SB), a specific inhibitor of p38-MAPK, protects pig myocardium against ischemic injury in an in vivo model. SB was applied by local infusion into the subsequently ischemic myocardium for 60 min before a 60-min period of coronary occlusion followed by 60-min reperfusion (index ischemia). Infarct size was reduced from a control value of 69.

Hypoxia-induced vascular endothelial growth factor expression precedes neovascularization after cerebral ischemia.

We investigated the hypothesis that hypoxia induces angiogenesis and thereby may counteract the detrimental neurological effects associated with stroke. Forty-eight to seventy-two hours after permanent middle cerebral artery occlusion we found a strong increase in the number of newly formed vessels at the border of the infarction. Using the hypoxia marker nitroimidazole EF5, we detected hypoxic cells in the ischemic border of the neocortex.

Angiogenesis in ischemic disease.

Angiogenic growth factors and their endothelial receptors function as major regulators of blood vessel formation. The VEGF/VEGFR and the Angiopoietin/Tie2 receptor systems represent key signal transduction pathways involved in the regulation of embryonic vascular development. Inactivation of any of the genes encoding these molecules results in defective vascular development and lethality between embryonic day 8.

The pathophysiology of the collateral circulation (arteriogenesis).

Since the mid 1980s a new strategy is coming from bench to bedside termed angiogenesis. This process involves sprouting of capillaries and finally results in newly developed microvessels which belong to the capillary level. Importantly these newly formed capillary tubes lack vascular smooth muscle cells, they are not surrounded by mural cells and are fragile and prone to rupture.

Responses of neurones of the rat suprachiasmatic nucleus to retinal illumination under photopic and scotopic conditions.

1. We have examined the responses of neurones in the suprachiasmatic nuclei (SCN) of the rat to retinal illumination under photopic and scotopic conditions to identify the types of photoreceptor input to these nuclei. 2.

The endothelial monocyte-activating polypeptide II (EMAP II) is a substrate for caspase-7.

Endothelial monocyte-activating polypeptide II (EMAP II) is a proinflammatory cytokine and a chemoattractant for leukocytes. The mature cytokine is formed in apoptotic cells by cleavage of the precursor proEMAP II. Here we show that caspase-7 is capable of cleaving proEMAP II in vitro.

Hypothermia abolishes hypoxia-induced hyperpermeability in brain microvessel endothelial cells.

The effect of mild (32 degrees C) and deep (22 degrees C) hypothermia on hypoxia-induced hyperpermeability was examined using an in vitro model of brain derived microvascular endothelial cells (BMEC). It was shown that hypoxia-induced hyperpermeability to inulin across the BMEC monolayer was completely abolished at 32 degrees C and 22 degrees C for up to 24 h of hypoxia. During normoxia, no influence of hypothermia on BMEC monolayer permeability was observed.