ALK1 loss results in vascular hyperplasia in mice and humans through PI3K activation
| العنوان: | ALK1 loss results in vascular hyperplasia in mice and humans through PI3K activation |
|---|---|
| المؤلفون: | Oriol Casanovas, Xavier Matias-Guiu, Miquel Angel Pujana, Agnès Figueras, Francesc Viñals, Carla Riera-Domingo, Luisa María Botella, Yaiza García-Ibáñez, Elisenda Alsina-Sanchís, Mariona Graupera, Ana M. Figueiredo, Antoni Riera-Mestre |
| المساهمون: | Universitat de Barcelona |
| المصدر: | Recercat. Dipósit de la Recerca de Catalunya instname Dipòsit Digital de la UB Universidad de Barcelona |
| بيانات النشر: | American Heart Association |
| مصطلحات موضوعية: | 0301 basic medicine, Vascular Endothelial Growth Factor A, Angiogenesis, Activin Receptors, Type II, Angiogenesis Inhibitors, Malalties vasculars, chemistry.chemical_compound, 0302 clinical medicine, Protein kinases, Growth Differentiation Factor 2, Medicine, Vascular diseases, Cells, Cultured, Rates (Animals de laboratori), Phosphoinositide-3 Kinase Inhibitors, Mice, Knockout, biology, Neovascularization, Pathologic, Factor de creixement de l'endoteli vascular, Hemorràgia, Vascular endothelial growth factor, Endothelial stem cell, Vascular endothelial growth factor A, medicine.anatomical_structure, Phenotype, Telangiectasia, Hereditary Hemorrhagic, Cardiology and Cardiovascular Medicine, Signal Transduction, Endothelium, Rats as laboratory animals, GDF2, Hemorrhage, Endoteli, Article, Retina, 03 medical and health sciences, Vascular endothelial growth factors, Human Umbilical Vein Endothelial Cells, PTEN, Animals, Humans, Genetic Predisposition to Disease, Protein Kinase Inhibitors, PI3K/AKT/mTOR pathway, Hyperplasia, business.industry, Endothelial Cells, Enzyme Activation, Mice, Inbred C57BL, Proteïnes quinases, 030104 developmental biology, chemistry, Case-Control Studies, Mutation, Cancer research, biology.protein, Retinal Telangiectasis, Phosphatidylinositol 3-Kinase, business, Activin Receptors, Type I, 030217 neurology & neurosurgery, Gene Deletion |
| الوصف: | Objective— ALK1 (activin-receptor like kinase 1) is an endothelial cell-restricted receptor with high affinity for BMP (bone morphogenetic protein) 9 TGF-β (transforming growth factor-β) family member. Loss-of-function mutations in ALK1 cause a subtype of hereditary hemorrhagic telangiectasia—a rare disease characterized by vasculature malformations. Therapeutic strategies are aimed at reducing potential complications because of vascular malformations, but currently, there is no curative treatment for hereditary hemorrhagic telangiectasia. Approach and Results— In this work, we report that a reduction in ALK1 gene dosage (heterozygous ALK1 +/ − mice) results in enhanced retinal endothelial cell proliferation and vascular hyperplasia at the sprouting front. We found that BMP9/ALK1 represses VEGF (vascular endothelial growth factor)-mediated PI3K (phosphatidylinositol 3-kinase) by promoting the activity of the PTEN (phosphatase and tensin homolog). Consequently, loss of ALK1 function in endothelial cells results in increased activity of the PI3K pathway. These results were confirmed in cutaneous telangiectasia biopsies of patients with hereditary hemorrhagic telangiectasia 2, in which we also detected an increase in endothelial cell proliferation linked to an increase on the PI3K pathway. In mice, genetic and pharmacological inhibition of PI3K is sufficient to abolish the vascular hyperplasia of ALK1 +/ − retinas and in turn normalize the vasculature. Conclusions— Overall, our results indicate that the BMP9/ALK1 hub critically mediates vascular quiescence by limiting PI3K signaling and suggest that PI3K inhibitors could be used as novel therapeutic agents to treat hereditary hemorrhagic telangiectasia. |
| وصف الملف: | application/pdf |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::2d4571338c7faa1695ff6a404f44cdc6Test http://hdl.handle.net/2445/124093Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....2d4571338c7faa1695ff6a404f44cdc6 |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |