VEGF-induced Rac1 activation in endothelial cells is regulated by the guanine nucleotide exchange factor Vav2

Vascular endothelial growth factor (VEGF) signaling is critical for both normal and disease-associated vascular development. Dysregulated VEGF signaling has been implicated in ischemic stroke, tumor angiogenesis, and many other vascular diseases. VEGF signals through several effectors, including the Rho family of small GTPases. As a member of this family, Rac1 promotes VEGF-induced endothelial cell migration by stimulating the formation of lamellipodia and membrane ruffles. To form these membrane protrusions, Rac1 is activated by guanine nucleotide exchange factors (GEFs) that catalyze the exchange of GDP for GTP. The goal of this study was to identify the GEF responsible for activating Rac1 in response to VEGF stimulation. We have found that VEGF stimulates biphasic activation of Rac1 and for these studies we focused on the peak of activation that occurs at 30 min. Inhibition of VEGFR-2 signaling blocks VEGF-induced Rac1 activation. Using a Rac1 nucleotide-free mutant (G15ARac1), which has a high affinity for binding activated GEFs, we show that the Rac GEF Vav2 associates with G15ARac1 after VEGF stimulation. Additionally, we show that depleting endothelial cells of endogenous Vav2 with siRNA prevents VEGF-induced Rac1 activation. Moreover, Vav2 is tyrosine phosphorylated upon VEGF treatment, which temporally correlates with Rac1 activation and requires VEGFR-2 signaling and Src kinase activity. Finally, we show that depressing Vav2 expression by siRNA impairs VEGF-induced endothelial cell migration. Taken together, our results provide evidence that Vav2 acts downstream of VEGF to activate Rac1

Short-term change in growth of uterine leiomyoma: tumor growth spurts

To describe the short-term changes in growth of uterine leiomyomata (fibroids)

Association of Genetic Variants and Incident Coronary Heart Disease in Multiethnic Cohorts: The PAGE Study

Genome wide association studies identified several single nucleotide polymorphisms (SNPs) associated with prevalent coronary heart disease (CHD) but less is known of associations with incident CHD. The association of thirteen published CHD SNPs was examined in five ancestry groups of four large US prospective cohorts

A Role for Sorting Nexin 2 in Epidermal Growth Factor Receptor Down-regulation: Evidence for Distinct Functions of Sorting Nexin 1 and 2 in Protein Trafficking

Sorting nexin 1 (SNX1) and SNX2, homologues of the yeast vacuolar protein-sorting (Vps)5p, contain a phospholipid-binding motif termed the phox homology (PX) domain and a carboxyl terminal coiled-coil region. A role for SNX1 in trafficking of cell surface receptors from endosomes to lysosomes has been proposed; however, the function of SNX2 remains unknown. Toward understanding the function of SNX2, we first examined the distribution of endogenous protein in HeLa cells. We show that SNX2 resides primarily in early endosomes, whereas SNX1 is found partially in early endosomes and in tubulovesicular-like structures distributed throughout the cytoplasm. We also demonstrate that SNX1 interacts with the mammalian retromer complex through its amino terminal domain, whereas SNX2 does not. Moreover, activated endogenous epidermal growth factor receptor (EGFR) colocalizes markedly with SNX2-positive endosomes, but minimally with SNX1-containing vesicles. To assess SNX2 function, we examined the effect of a PX domain-mutated SNX2 that is defective in vesicle localization on EGFR trafficking. Mutant SNX2 markedly inhibited agonist-induced EGFR degradation, whereas internalization remained intact. In contrast, SNX1 PX domain mutants failed to effect EGFR degradation, whereas a SNX1 deletion mutant significantly inhibited receptor down-regulation. Interestingly, knockdown of SNX1 and SNX2 expression by RNA interference failed to alter agonist-induced EGFR down-regulation. Together, these findings suggest that both SNX1 and SNX2 are involved in regulating lysosomal sorting of internalized EGFR, but neither protein is essential for this process. These studies are the first to demonstrate a function for SNX2 in protein trafficking

Short-term change in growth of uterine leiomyoma: tumor growth spurts

OBJECTIVE: To describe the short-term changes in growth of uterine leiomyomata (fibroids). DESIGN: Prospective observational study SETTING: University Research Center PATIENTS: Premenopausal women with fibroids (n = 18 blacks and 18 whites) recruited through a physician network and community outreach. INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURES: The volumes of 101 fibroids were measured at enrollment, 3, 6, and 12 months with magnetic resonance imaging (MRI), resulting in three interval-specific growth rates. Growth spurts were defined by interval growth rates ≥ 30% per 3 months and substantially greater than during other intervals of observation. An overall measure of short-term change in fibroid growth was calculated as the variance of the three interval-specific growth rates. RESULTS: Growth spurts were observed in 37 of the 101 fibroids, a prevalence nearly 10 times higher than that attributable to potential measurement error. Fibroids from the same women did not have similar short-term growth (p=0.27), nor were woman-specific factors (age, race/ethnicity, parity, body mass) or the fibroid position in the uterus important. However, large fibroids (>5 cm diameter) had less short-term change than smaller fibroids (p<0.001). CONCLUSIONS: Short spurts of growth are common for fibroids, suggesting that tumor biology may change rapidly

Incidence of typhoid fever in Burkina Faso, Democratic Republic of the Congo, Ethiopia, Ghana, Madagascar, and Nigeria (the Severe Typhoid in Africa programme) : a population-based study

Abstract: Background Typhoid Fever remains a major cause of morbidity and mortality in low-income settings. The Severe Typhoid in Africa programme was designed to address regional gaps in typhoid burden data and identify populations eligible for interventions using novel typhoid conjugate vaccines. Methods A hybrid design, hospital -based prospective surveillance with population -based health-care utilisation surveys, was implemented in six countries in sub-Saharan Africa. Patients presenting with fever (>= 375 degrees C axillary or >= 380 degrees C tympanic) or reporting fever for three consecutive days within the previous 7 days were invited to participate. Typhoid fever was ascertained by culture of blood collected upon enrolment. Disease incidence at the population level was estimated using a Bayesian mixture model. Findings 27 866 (338%) of 82 491 participants who met inclusion criteria were recruited. Blood cultures were performed for 27 544 (988%) of enrolled participants. Clinically significant organisms were detected in 2136 (77%) of these cultures, and 346 (162%) Salmonella enterica serovar Typhi were isolated. The overall adjusted incidence per 100 000 person -years of observation was highest in Kavuaya and Nkandu 1, Democratic Republic of the Congo (315, 95% credible interval 254-390). Overall, 46 (164%) of 280 tested isolates showed ciprofloxacin non -susceptibility. Interpretation High disease incidence (ie, >100 per 100 000 person -years of observation) recorded in four countries, the prevalence of typhoid hospitalisations and complicated disease, and the threat of resistant typhoid strains strengthen the need for rapid dispatch and implementation of effective typhoid conjugate vaccines along with measures designed to improve clean water, sanitation, and hygiene practices. Funding The Bill & Melinda Gates Foundation. Copyright (c) 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license