An integrin-contactin complex regulates CNS myelination by differential Fyn phosphorylation.

The understanding of how adhesion molecules mediate the axon-glial interactions in the CNS that ensure target-dependent survival of oligodendrocytes and initiate myelination remains incomplete. Here, we investigate how signals from adhesion molecules can be integrated to regulate these initial steps of myelination. We first demonstrate that the Ig superfamily molecule contactin is associated in oligodendrocytes with integrins, extracellular matrix receptors that regulate target-dependent survival by amplification of growth factor signaling. This amplification is inhibited by small interfering RNA-mediated knockdown of contactin in oligodendrocytes. In contrast, the presence of L1-Fc, the extracellular portion of a contactin ligand expressed on axons, enhanced survival and additionally promoted myelination in cocultures of neurons and oligodendrocytes. We further demonstrate that the signals from contactin and integrin are integrated by differential phosphorylation of the Src family kinase Fyn. Integrin induced dephosphorylation of the inhibitory Tyr-531, whereas contactin increased phosphorylation of both Tyr-531 and the activating Tyr-420. The combined effect is an enhanced activity of Fyn and also a dynamic regulation of the phosphorylation/dephosphorylation balance of Fyn, as required for normal cell adhesion and spreading. We conclude, therefore, that a novel integrin/contactin complex coordinates signals from extracellular matrix and the axonal surface to regulate both oligodendrocyte survival and myelination by controlling Fyn activity.

Do changes in gastro-intestinal blood flow explain high-altitude anorexia?

BACKGROUND: Gastrointestinal symptoms are common on acute exposure to high-altitude (HA). Underlying mechanisms are not understood, but vascular shunting away from the gut could be responsible. Therefore, blood flow in the superior mesenteric artery (SMA) and hepatic portal vein (HPV) was examined at sea level (SL) and after ascent to 4392 m (HA). MATERIALS AND METHODS: Twelve subjects [eight male, mean age 40 (22-72) years] were studied following an overnight fast and a standard meal. Cross-sectional vessel area and blood velocity were measured by ultrasound, systolic and diastolic flow calculated for the SMA (HR x vessel area x velocity, cm(3) min(-1)) and mean flow for the HPV. RESULTS: All subjects experienced reduced appetite at HA. Blood flow in the SMA and HPV increased following food at SL (mean SMA systolic flow 1024 vs. 3316 cm(3) min(-1), P < 0.001; HPV 505 vs. 1789, P < 0.001) and at HA (2020 vs. 3767, P < 0.001; HPV 708 vs. 1727, P < 0.001). Pre-prandial flow in the SMA and HPV was significantly increased at HA compared with SL. The changes were due to increased vessel diameter and increased flow velocity. There was no difference in post-prandial flow between SL and HA in the HPV, although the increase in post-prandial flow was greater at SL than HA (254% increase vs. 144%). CONCLUSIONS: These results show that resting blood flow in the gastrointestinal tract is increased during exposure to high-altitude hypoxia, and that the vascular response of increased blood flow following food ingestion is maintained. Therefore, reduced flow is unlikely to cause gastrointestinal symptoms and reduced appetite at HA.

Translation of myelin basic protein mRNA in oligodendrocytes is regulated by integrin activation and hnRNP-K.

Myelination in the central nervous system provides a unique example of how cells establish asymmetry. The myelinating cell, the oligodendrocyte, extends processes to and wraps multiple axons of different diameter, keeping the number of wraps proportional to the axon diameter. Local regulation of protein synthesis represents one mechanism used to control the different requirements for myelin sheath at each axo-glia interaction. Prior work has established that ß1-integrins are involved in the axoglial interactions that initiate myelination. Here, we show that integrin activation regulates translation of a key sheath protein, myelin basic protein (MBP), by reversing the inhibitory effect of the mRNA 3'UTR. During oligodendrocyte differentiation and myelination α6ß1-integrin interacts with hnRNP-K, an mRNA-binding protein, which binds to MBP mRNA and translocates from the nucleus to the myelin sheath. Furthermore, knockdown of hnRNP-K inhibits MBP protein synthesis during myelination. Together, these results identify a novel pathway by which axoglial adhesion molecules coordinate MBP synthesis with myelin sheath formation.

Intrapulmonary and intracardiac shunting with exercise at altitude.

Recent studies in normal participants have shown that right to left shunt blood vessels in the lung open up during exercise. We describe the first field study to investigate this phenomenon at altitude. This study aimed to assess the effect of altitude and partial acclimatization on inducible right to left shunting at rest and with exercise. A contrast-enhanced transcranial Doppler imaging technique to detect microbubbles after injection of blood and saline agitated with air was used to measure right to left shunting in 10 normal participants at rest and immediately after exercising to maximum oxygen consumption (VO(2max)) at 80 m, on acute exposure to 3450 m, and finally after a week above 3450 m. At 80 m, exercising resulted in right to left shunting via patent foramen ovale in 2 participants, but there was no evidence of shunting in the remaining 8 participants. Cerebral microbubbles were detected at rest in the 2 participants with patent foramen ovale on acute exposure to 3450 m, and the shunting increased on exercise (P = .04). In 5 of the remaining 8 participants without patent foramen ovale, cerebral microbubbles were detected on exercise (P = .04) but not at rest. Partial acclimatization had minimal effect on the prevalence or magnitude of the intrapulmonary or intracardiac shunts. Oxygenation was similar in those with shunts compared with those without shunts. Intrapulmonary shunting occurs on exercise at altitude, but the clinical and physiologic significances have yet to be determined. Despite the occurrence of shunting in most participants, our results suggest that this phenomenon is not a significant factor in altitude and exercise-induced hypoxia.

Effect of sildenafil and acclimatization on cerebral oxygenation at altitude.

Phosphodiesterase-5 inhibitors decrease hypoxic pulmonary vasoconstriction under hypobaric hypoxia, but are not known to affect cerebral blood flow or oxygenation. The present study was designed to evaluate the effect of sildenafil on cerebral haemodynamics during acute exposure to altitude and after acclimatization. Ten subjects were studied 1 and 3 days after rapid ascent to 3480 m before and for two consecutive hours after taking sildenafil (50 mg). Before acclimatization, HR (heart rate) rose at 1 h (76.3+/-1.0 beats/min compared with 72.5+/-1.5 beats/min at baseline; P<0.05) and had returned to baseline at 2 h (71.3+/-1.1 beats/min; P>0.05). Mean BP (blood pressure) fell from 96.0+/-2.0 mmHg at baseline to 91.7+/-2.5 (P<0.001) at 1 h and 89.8+/-1.8 mmHg (P<0.0001) at 2 h, whereas SaO2 (arterial oxygen saturation) increased from 83.9+/-0.5% at baseline to 85.3+/-0.4% (P<0.0001) at 1 h and 85.0+/-0.5% (P<0.01) at 2 h. MCAV [MCA (middle cerebral artery) velocity] and PETCO2 (end-tidal partial pressure of CO2) were unchanged, but rSO2 (regional cerebral oxygen saturation) rose progressively at 1 h (62.7+/-0.8%; P<0.05) and 2 h (65.3+/-0.9%; P<0.0001) compared with baseline (59.3+/-1.3%). After 3 days of acclimatization, resting rSO2 and RMCA (MCA resistance) increased and oxygen delivery fell. Changes in HR and mean BP after sildenafil were similar to day 1, but SaO2 did not change. However, rSO2 increased [61.7+/-0.9% at baseline to 65.0+/-1.0% (P<0.0001) at 1 h and 64.0+/-0.9% (P<0.001) at 2 h], despite a reduction in MCAV [65.3+/-1.8 cm/s at baseline to 61.3+/-1.5 cm/s (P<0.01) at 1 h and 60.9+/-1.7 cm/s (P<0.0001) at 2 h] and PETCO2 [4.1+/-0.05 kPa at baseline to 4.0+/-0.04 kPa at 2 h (P<0.01)]. These observations suggest that sildenafil improves cerebral oxygenation at altitude. Whereas the early changes before acclimatization may be largely pulmonary in origin, the later observations may be a direct cerebral effect which warrants further study.