Circulating anti-angiogenic factors during hypertensive pregnancy and increased risk of respiratory distress syndrome in preterm neonates

Objective: To test the hypothesis that high circulating concen-trations of maternal anti-angiogenic factors are associated with increased risk of respiratory distress syndrome (RDS). Study Design: This is a nested case-control study of nulliparous women who delivered less than 37 weeks of gestation within the Calcium for Preeclampsia Prevention (CPEP) trial. The study included 116 women with preeclampsia or gestational hyperten-sion and 323 normotensive controls. Soluble fms-like tyrosine kinase 1 (sFlt1), placental growth factor (PlGF) and soluble endo-glin (sEng) in maternal serum were measured at 21–32 weeks of gestation. Results: Preterm infants born to hypertensive mothers were more likely to develop RDS (22.5% vs. 20.9%, p =0.03). After adjustment for gestational age at delivery, the odds ratio for the relationship between hypertension in pregnancy and RDS was 2.18 (95% CI 1.08–4.39). In hypertensive pregnancies women whose infants developed RDS had significantly higher circulating mean sFlt1 levels during midpregnancy (21–32 weeks of gestation) even after adjustment for gestational age at delivery (21,516 pg/mL vs. 7,000 pg/mL, p =0.01). Conclusions: Preterm preeclampsia and gestational hypertension, charac-terized by high circulating levels of sFlt1, are associated with a twofold increased risk of RDS in infants delivered before 37 weeks. Among women with these hypertensive pregnancies circulating sFlt1 concentrations during midpregnancy were substantially higher in women whose infants developed RDS

Release of cellular tension signals self-restorative ventral lamellipodia to heal barrier micro-wounds

Basic mechanisms by which cellular barriers sense and respond to integrity disruptions remain poorly understood. Despite its tenuous structure and constitutive exposure to disruptive strains, the vascular endothelium exhibits robust barrier function. We show that in response to micrometer-scale disruptions induced by transmigrating leukocytes, endothelial cells generate unique ventral lamellipodia that propagate via integrins toward and across these “micro-wounds” to close them. This novel actin remodeling activity progressively healed multiple micro-wounds in succession and changed direction during this process. Mechanical probe-induced micro-wounding of both endothelia and epithelia suggests that ventral lamellipodia formed as a response to force imbalance and specifically loss of isometric tension. Ventral lamellipodia were enriched in the Rac1 effectors cortactin, IQGAP, and p47Phox and exhibited localized production of hydrogen peroxide. Together with Apr2/3, these were functionally required for effective micro-wound healing. We propose that barrier disruptions are detected as local release of isometric tension/force unloading, which is directly coupled to reactive oxygen species–dependent self-restorative actin remodeling dynamics

Reduced angiogenic responses in adult Endoglin heterozygous mice

10 páginas, 5 figuras -- PAGS nros. 845-854Objective: To determine if angiogenesis is altered in adult Endoglin heterozygous (Eng+/−) mice, the animal model for the vascular disorder hereditary hemorrhagic telangiectasia type 1 (HHT1). Methods: Primary cultures of endothelial cells were generated from Eng+/− and Eng+/+ mice and analyzed for proliferation, migration, and ability to form capillary-like tubes. Endothelial cells derived from umbilical veins of newborns (HUVEC) with an HHT1 genotype were also tested for capillary formation. Two in vivo models of angiogenesis were tested in the Eng+/− and Eng+/+ mice: Matrigel implant-dependent angiogenesis and reperfusion following hindlimb ischemia. Results: The Eng+/− endothelial cells displayed significantly reduced proliferation and migration, increased collagen production, and decreased NO synthase expression and vascular endothelial growth factor (VEGF) secretion. They also showed impaired capillary tube formation in vitro, as did the HHT1 HUVEC. These endothelial cell-specific abnormalities were associated with impaired Matrigel-dependent capillary tube formation in vivo and delayed reperfusion following hindlimb ischemia. Conclusions: Although vascular development is normal in Eng+/− mice, angiogenic abnormalities were observed in the adult mice and their isolated endothelial cells. These results suggest that a normal level of endoglin is required for full angiogenic activityThis study was supported by grants from Comisión Interministerial de Ciencia y Tecnología, (SAF2001/1701 and BFU2004-00285/BFI to JMLN and SAF2004-01390 to CB), Fondo de Investigación Sanitaria (PI020200 to CB), HHT Foundation International (CB) and The Heart and Stroke Foundation of Canada (ML). Dr. M. Jerkic was supported by a Fellowship from Instituto Reina Sofía de Investigación Nefrológica. Marta Prieto and Miguel Pericacho are fellows of Junta de Castilla y LeonPeer reviewe