Increased glycolysis in the lung vasculature has been connected to the development of pulmonary hypertension (PH). We therefore investigated whether glycolytic regulator 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase (PFKFB3)-mediated endothelial glycolysis plays a critical role in the development of PH. Heterozygous global deficiency of Pfkfb3 protected mice from developing hypoxia-induced PH, and administration of the PFKFB3 inhibitor 3PO almost completely prevented PH in rats treated with Sugen 5416/hypoxia, indicating a causative role of PFKFB3 in the development of PH. Immunostaining of lung sections and Western blot with isolated lung endothelial cells showed a dramatic increase in PFKFB3 expression and activity in pulmonary endothelial cells of rodents and humans with PH. We generated mice that were constitutively or inducibly deficient in endothelial Pfkfb3 and found that these mice were incapable of developing PH or showed slowed PH progression. Compared with control mice, endothelial Pfkfb3-knockout mice exhibited less severity of vascular smooth muscle cell proliferation, endothelial inflammation, and leukocyte recruitment in the lungs. In the absence of PFKFB3, lung endothelial cells from rodents and humans with PH produced lower levels of growth factors (such as PDGFB and FGF2) and proinflammatory factors (such as CXCL12 and IL1β). This is mechanistically linked to decreased levels of HIF2A in lung ECs following PFKFB3 knockdown. Taken together, these results suggest that targeting PFKFB3 is a promising strategy for the treatment of PH.

Centrifuge modelling tests show clearly the phase change in lateral acceleration in the backfill behind a retaining wall as shear waves propagate from the base of the model towards the ground surface. However, design calculations for the dynamic lateral earth pressure on a retaining wall which use a pseudo-static approach assume that the backfill experiences a uniform acceleration throughout. Researchers have agreed that the total lateral earth pressure calculated using this approach is approximately correct, but have disagreed over the distribution of the dynamic increment of pressure. The Paper presents an analysis which takes into account a finite shear wave velocity in the backtill, thus allowing for the phase change in a prototype structure. The phase change does not have a significant influence on the magnitude of the total earth pressure, but it has a marked effect on the distribution of the dynamic increment. The resultant pressure is seen to act at a point above one third of the height of the wall. The maximum dynamic earth pressure and the peak bending moment on the wall are approximately in phase with the acceleration at mid-depth, and therefore this acceleration may be the most appropriate value to nse for design. The effect of a non-uniform shear modulus distribution is considered, as is the effect of amplification of acceleration on the distribution and magnitude of earth pressure. Ampliication of acceleration has an influence similar in character to the effect of increasing the acceleration coefftcient in a uniform acceleration field. Centrifuge model test data analysed using this approach show good agreement if the amplification of motion is taken into account. KEYWORDS:analysis; centrifuge modelling; earth pressure; ear&quakes; retaining walls; soilstructure interaction.Des es&s de modele i la centrifugeuse indiquent clairemeat le changement de phase de l'acceleration laterale dans le remblai derriere un mur de soutenement pendant que les ondes de cisaillement se propagent 1 partir de la base du modhle vers la surface du terrain. Les calculs classiques pour la pression laterale dynamique des terres sur un mur de soutenement qui emploient un methode pseudostatique admettent cependant que le remblai entier subit une acceleration uniforme. Les rechercheurs reconnaissent que la pression laterale totale des terres calculb par cette methode est approximativement correcte, mais ne sont pas d'accord sur la distribution de l'incremeot dynamique de pression. L'article prbente une analyse qui inclut une velocite finie de l'onde de cisaillement dans le remblai. Le changement de phase darts une structure prototype eat ainsi pris en compte. Le changement de phase est pratiquement sans influence sur la valeur totale de la pression des terres, tandis qu'il prod& un effet marque sur la distribution de l'increment dynamique. On observe que la pression r6sultante s'applique au-dessus du tiers de la hauteur du mur. La pression maximale dynamique des terres et le moment maximal de flexion sur le mur se trouvent appro...

Increased aerobic glycolysis in endothelial cells of atheroprone areas of blood vessels has been hypothesized to drive increased inflammation and lesion burden but direct links remain to be established. Here we show that endothelial cells exposed to disturbed flow in vivo and in vitro exhibit increased levels of protein kinase AMP-activated (PRKA)/AMP-activated protein kinases (AMPKs). Selective deletion of endothelial Prkaa1, coding for protein kinase AMP-activated catalytic subunit alpha1, reduces glycolysis, compromises endothelial cell proliferation, and accelerates the formation of atherosclerotic lesions in hyperlipidemic mice. Rescue of the impaired glycolysis in Prkaa1-deficient endothelial cells through Slc2a1 overexpression enhances endothelial cell viability and integrity of the endothelial cell barrier, and reverses susceptibility to atherosclerosis. In human endothelial cells, PRKAA1 is upregulated by disturbed flow, and silencing PRKAA1 reduces glycolysis and endothelial viability. Collectively, these results suggest that increased glycolysis in the endothelium of atheroprone arteries is a protective mechanism.