title: Phosphoinositide 3-kinase β mediates microvascular endothelial repair of thrombotic microangiopathy.
abstract: Thrombotic microangiopathy (TMA) commonly involves injury of kidney glomerular endothelial cells (ECs) and fibrin occlusion of the capillaries. The mechanisms underlying repair of the microvasculature and recovery of kidney function are poorly defined. In the developing vasculature, the phosphoinositide 3-kinase (PI3K) α isoform integrates many growth factor cues. However, the role of individual isoforms in repair of the established vasculature is unclear. We found that postnatal endothelial deletion of PI3Kβ sensitizes mice to lethal acute kidney failure after TMA injury. In vitro, PI3Kβ-deficient ECs show reduced angiogenic invasion of fibrin matrix with unaltered sensitivity to proapoptotic stress compared with wild-type ECs. This correlates with decreased expression of the EC tip cell markers apelin and Dll4 and is associated with a reduction in migration and proliferation. In vivo, PI3Kβ-knockdown ECs are deficient in assembly of microvessel-like structures. These data identify a critical role for endothelial PI3Kβ in microvascular repair following injury.
authors.affiliation: Department of Medicine.
authors.forename: George
authors.initials: G
authors.lastname: Haddad
authors.affiliation: Department of Medicine.
authors.forename: Pavel
authors.initials: P
authors.lastname: Zhabyeyev
authors.affiliation: Department of Medicine.
authors.forename: Maikel
authors.initials: M
authors.lastname: Farhan
authors.affiliation: Department of Surgery.
authors.forename: Lin Fu
authors.initials: LF
authors.lastname: Zhu
authors.affiliation: Department of Physiology, and.
authors.forename: Zamaneh
authors.initials: Z
authors.lastname: Kassiri
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Alberta, Edmonton, AB, Canada; and.
authors.forename: David C
authors.initials: DC
authors.lastname: Rayner
authors.affiliation: University College London Cancer Institute, University College London, London, United Kingdom.
authors.forename: Bart
authors.initials: B
authors.lastname: Vanhaesebroeck
authors.affiliation: Department of Medicine.
authors.forename: Gavin Y
authors.initials: GY
authors.lastname: Oudit
authors.affiliation: Department of Medicine.
authors.forename: Allan G
authors.initials: AG
authors.lastname: Murray
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D015415:Biomarkers; D058541:Class II Phosphatidylinositol 3-Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology*; D004789:Enzyme Activation; D006801:Humans; D007678:Kidney Glomerulus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D055806:Microvessels / Q000378:metabolism* / Q000473:pathology*; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D057049:Thrombotic Microangiopathies / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
chemical_list: D015415:Biomarkers; D042461:Vascular Endothelial Growth Factor A; D058541:Class II Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase