LRP1-Dependent Endocytic Mechanism Governs the Signaling Output of the Bmp System in Endothelial Cells and in Angiogenesis

Rationale: Among the extracellular modulators of Bmp (bone morphogenetic protein) signaling, Bmper (Bmp endothelial cell precursor-derived regulator) both enhances and inhibits Bmp signaling. Recently we found that Bmper modulates Bmp4 activity via a concentration-dependent, endocytic trap-and-sink mechanism. Objective: To investigate the molecular mechanisms required for endocytosis of the Bmper/Bmp4 and signaling complex and determine the mechanism of Bmper's differential effects on Bmp4 signaling. Methods and Results: Using an array of biochemical and cell biology techniques, we report that LRP1 (LDL receptor-related protein 1), a member of the LDL receptor family, acts as an endocytic receptor for Bmper and a coreceptor of Bmp4 to mediate the endocytosis of the Bmper/Bmp4 signaling complex. Furthermore, we demonstrate that LRP1-dependent Bmper/Bmp4 endocytosis is essential for Bmp4 signaling, as evidenced by the phenotype of lrp1-deficient zebrafish, which have abnormal cardiovascular development and decreased Smad1/5/8 activity in key vasculogenic structures. Conclusions: Together, these data reveal a novel role for LRP1 in the regulation of Bmp4 signaling by regulating receptor complex endocytosis. In addition, these data introduce LRP1 as a critical regulator of vascular development. These observations demonstrate Bmper's ability to fine-tune Bmp4 signaling at the single-cell level, unlike the spatial regulatory mechanisms applied by other Bmp modulators.     

Modulation of neuroplastic changes and corticotropin-releasing factor-associated behavior by a phylogenetically ancient and conserved peptide family

The co-evolution of peptides and early cells some 3.7 billion years ago provided bioactive peptides with a long history for the proliferation and refinement of peptide hormones. Central to the adaptation and evolution of cell types in metazoans is the development of peptide signaling systems that regulate stress mechanisms. The corticotropin-releasing factor (CRF) family of peptides represents the canonical family of peptides that are pivotal to the regulation of stress in vertebrates. However, these peptides appear to have evolved at least 2 billion years after the formation of the first postulated bioactive peptides, suggesting that before this, other peptide systems played a role in stress and energy metabolism. The teneurin C-terminal associated peptides (TCAPs) are a recently discovered family of highly conserved peptides that are processed from the teneurin transmembrane proteins. This peptide/protein system is ubiquitous in multicellular organisms and evolved before the CRF family. TCAP-1 is a potent regulator of CRF-associated physiology and behavior and may play a significant role in the regulation of cell-to-cell communication and neuroplasticity in neurons.     

Genetic determinants of 5-lipoxygenase pathway in a Spanish population and their relationship with cardiovascular risk

ObjectiveLeukotrienes (LT) play a role in inflammation, cardiovascular diseases, and cancer. Although some studies suggest that there are genes that determine variability of some LT-related phenotypes, the genetic influence on these phenotypes has not been evaluated.MethodsThe relative contributions of genetic and environmental influences to the 5-lipoxygenase pathway-related phenotypes (5-Lipoxygenase, five lipoxygenase activating protein (FLAP), LTA₄-hydrolase and LTC₄-synthase expression, and LTB₄-plasma concentration and LTB₄ production by stimulated whole blood) were assessed in a sample of 934 individuals in 35 extended families. Our design is based on extended families recruited through a probands with idiopathic thrombophilia. This strategy allows us the analysis of the effects of measured covariates (such as sex, age and smoking), genes, and environmental variables shared by members of a household.ResultsAll of these phenotypes showed significant genetic contributions, with heritabilities ranging from 0.33 to 0.51 for enzyme expression and from 0.25 to 0.50 for LTB₄ production of the residual phenotypic variance. Significant phenotypic and genetic correlation among the LT-related traits was found. More importantly, FLAP and LTA₄-hydrolase expression exhibit significant genetic correlations with arterial thrombosis, indicating that some of the genes that influence quantitative variation in these phenotypes also influence the risk of thrombosis.ConclusionThis is the first study that quantifies the genetic component of 5-Lipoxygenase pathway phenotypes. The high heritability of these traits and the significant genetic correlations between arterial thrombosis and some of these phenotypes suggest that the exploitation of correlated quantitative phenotypes will aid the search for susceptibility genes.