title: Endothelial Rictor is crucial for midgestational development and sustained and extensive FGF2-induced neovascularization in the adult.
abstract: To explore the general requirement of endothelial mTORC2 during embryonic and adolescent development, we knocked out the essential mTORC2 component Rictor in the mouse endothelium in the embryo, during adolescence and in endothelial cells in vitro. During embryonic development, Rictor knockout resulted in growth retardation and lethality around embryonic day 12. We detected reduced peripheral vascularization and delayed ossification of developing fingers, toes and vertebrae during this confined midgestational period. Rictor knockout did not affect viability, weight gain, and vascular development during further adolescence. However during this period, Rictor knockout prevented skin capillaries to gain larger and heterogeneously sized diameters and remodeling into tortuous vessels in response to FGF2. Rictor knockout strongly reduced extensive FGF2-induced neovascularization and prevented hemorrhage in FGF2-loaded matrigel plugs. Rictor knockout also disabled the formation of capillary-like networks by FGF2-stimulated mouse aortic endothelial cells in vitro. Low RICTOR expression was detected in quiescent, confluent mouse aortic endothelial cells, whereas high doses of FGF2 induced high RICTOR expression that was associated with strong mTORC2-specific protein kinase Cα and AKT phosphorylation. We demonstrate that the endothelial FGF-RICTOR axis is not required during endothelial quiescence, but crucial for midgestational development and sustained and extensive neovascularization in the adult.
authors.affiliation: Department of Internal Medicine, University Hospital, CH-8091 Zürich, Switzerland.
authors.forename: Fabio
authors.initials: F
authors.lastname: Aimi
authors.affiliation: Department of Internal Medicine, University Hospital, CH-8091 Zürich, Switzerland.
authors.forename: Stavroula
authors.initials: S
authors.lastname: Georgiopoulou
authors.affiliation: Department of Internal Medicine, University Hospital, CH-8091 Zürich, Switzerland.
authors.forename: Ina
authors.initials: I
authors.lastname: Kalus
authors.affiliation: Department of Internal Medicine, University Hospital, CH-8091 Zürich, Switzerland.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Lehner
authors.affiliation: Division of Plastic and Reconstructive Surgery, University Hospital, CH-8091 Zürich, Switzerland.
authors.forename: Alica
authors.initials: A
authors.lastname: Hegglin
authors.affiliation: Division of Visceral and Transplant Surgery, University Hospital, CH-8091 Zürich, Switzerland.
authors.forename: Përparim
authors.initials: P
authors.lastname: Limani
authors.affiliation: Department of Internal Medicine, University Hospital, CH-8091 Zürich, Switzerland.
authors.forename: Vinicius
authors.initials: V
authors.lastname: Gomes de Lima
authors.affiliation: Biozentrum, University of Basel, CH-4057 Basel, Switzerland.
authors.forename: Markus A
authors.initials: MA
authors.lastname: Rüegg
authors.affiliation: Biozentrum, University of Basel, CH-4057 Basel, Switzerland.
authors.forename: Michael N
authors.initials: MN
authors.lastname: Hall
authors.affiliation: Division of Plastic and Reconstructive Surgery, University Hospital, CH-8091 Zürich, Switzerland.|Zürich Center for Integrative Human Physiology, University of Zürich, Switzerland.
authors.forename: Nicole
authors.initials: N
authors.lastname: Lindenblatt
authors.affiliation: Department of Internal Medicine, University Hospital, CH-8091 Zürich, Switzerland.
authors.forename: Elvira
authors.initials: E
authors.lastname: Haas
authors.affiliation: Department of Internal Medicine, University Hospital, CH-8091 Zürich, Switzerland.|Zürich Center for Integrative Human Physiology, University of Zürich, Switzerland.|Center of Competence Multimorbidity and University Research Priority Program "Dynamics of Healthy Aging", University of Zurich, Switzerland.
authors.forename: Edouard J
authors.initials: EJ
authors.lastname: Battegay
authors.affiliation: Department of Internal Medicine, University Hospital, CH-8091 Zürich, Switzerland.|Zürich Center for Integrative Human Physiology, University of Zürich, Switzerland.
authors.forename: Rok
authors.initials: R
authors.lastname: Humar
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000235:genetics; D047108:Embryonic Development / Q000235:genetics*; D004727:Endothelium / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000096:biosynthesis / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D006470:Hemorrhage / Q000235:genetics / Q000473:pathology; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000235:genetics*; D010766:Phosphorylation; D051571:Protein Kinase C-alpha / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D046912:Multiprotein Complexes; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; C525637:rictor protein, mouse; D016222:Fibroblast Growth Factor 2; D000076225:Mechanistic Target of Rapamycin Complex 2; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C496630:Prkca protein, mouse; D051571:Protein Kinase C-alpha