The semaphorins are a family of secreted or membranebound proteins that are known to guide axons in the developing nervous system. Genetic evidence revealed that a class III semaphorin, semaphorin 3E (Sema3E), and its receptor Plexin-D1 also control the vascular patterning during development. At the molecular level, we have recently shown that Sema3E acts on Plexin-D1 expressed in endothelial cells, thus initiating a novel antiangiogenic signaling pathway that results in the retraction of filopodia in endothelial tip cells. Sema3E induces the rapid disassembly of integrin-mediated adhesive structures, thereby inhibiting endothelial cell adhesion to the extracellular matrix. This process requires the activation of small GTPase Arf6 (ADPribosylation factor 6), which regulates intracellular trafficking of 1 integrin. However, the molecular mechanisms by which Sema3E-Plexin-D1 activates Arf6 remained to be identified. Here we show that GEP100 (guanine nucleotide exchange protein 100)/Brag2, a guanine nucleotide exchange factor for Arf6, mediates Sema3E-induced Arf6 activation in endothelial cells. We provide evidence that upon activation by Sema3E, Plexin-D1 recruits phosphatidylinositol-4-phosphate 5-kinase, and its enzymatic lipid product, phosphatidylinositol 4,5-bisphosphate, binds to the pleckstrin homology domain of GEP100. Phosphatidylinositol 4,5-bisphosphate binding to GEP100 enhances its guanine nucleotide exchange factor activity toward Arf6, thus resulting in the disassembly of integrinmediated focal adhesions and endothelial cell collapse. Our present study reveals a novel phospholipid-regulated antiangiogenic signaling pathway whereby Sema3E activates Arf6 through Plexin-D1 and consequently controls integrin-mediated endothelial cell attachment to the extracellular matrix and migration.Angiogenesis, the formation of new blood capillaries from pre-existing ones, is an essential process during embryonic development. In adults, angiogenesis is required for tissue repair during physiological wound healing, whereas dysregulated angiogenesis contributes to a variety of pathological conditions, such as diabetic retinopathy, age-related macular degeneration, rheumatoid arthritis, and cancer (1). Hence, the identification of molecular mechanisms controlling normal and aberrant angiogenesis may afford new therapeutic opportunities for multiple human diseases (2). In this regard, recent studies revealed that axon guidance molecules, including netrin, slit, eph, and semaphorins, play a key role in developmental and postnatal angiogenesis (3). Among them, multiple secreted class III semaphorins (Sema3s) 4 are reported to control endothelial cell migration in vitro and in vivo (4 -7). Sema3s signal through A-type and D-type Plexin family proteins (Plexin-A1, -A2, and -A3 and Plexin-D1) and utilize their coreceptor neuropilins (Nrp1 and Nrp2) to tightly control proand antiangiogenic responses (8). However, the downstream signaling pathways initiated by these semaphorin receptors are complex and not fully understood,...
A retrospective review of 3,265,894 veterans seen over a 5-year period demonstrates dry eye is associated with numerous chronic pain conditions implying shared mechanisms.
DE and pain disorders occur at higher frequencies in patients with a diagnosis of TBI, suggesting a common underlying pathophysiology.
Dry eye (DE) and allergic conjunctivitis may present similarly, and it remains unclear whether some individuals have an underlying allergic component to their DE. To better understand this relationship, we performed a cross-sectional study in 75 individuals with DE symptoms and/or signs. Immunoglobulin E (IgE) levels in tear samples were quantified and home environmental exposures assessed via standardized survey. Tears were collected by Schirmer strip, and total tear IgE levels were quantified using enzyme-linked immunosorbent assay (ELISA). Data were analyzed using descriptive statistics and linear and logistic regressions. The main outcome measures were total tear IgE levels and their association with environmental exposures. The mean age of the subjects was 66.2 ± 7.8 years. Sixty-two individuals had dry eye symptoms (Dry Eye Questionnaire-5 ≥ 6), and 75 had one or more signs of DE. Detectable total tear IgE levels were observed in 76% of subjects, and 17.3% had high levels (>1 ng/mL). Individuals with exposure to pet(s) (odds ratio (OR) 11.5, p = 0.002) and smoke (OR 38.6, p = 0.008) at home were more likely to have high IgE levels compared to those not exposed. Individuals with tears collected during spring or summer were 3.9 times (p = 0.028) more likely to have high IgE compared to those sampled at other times of year. Subjects born in the US were 3.45 times (p = 0.010) more likely to have high IgE compared to individuals born outside the US. To conclude, a majority of individuals with DE symptoms and/or signs had detectable IgE levels in their tears. High tear IgE levels were correlated with allergy season and exposures in the home linked with allergy.
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