title: Abl kinases are required for vascular function, Tie2 expression, and angiopoietin-1-mediated survival.
abstract: Endothelial dysfunction is associated with diverse cardiovascular pathologies. Here, we show a previously unappreciated role for the Abelson (Abl) family kinases (Abl and Arg) in endothelial function and the regulation of angiogenic factor pathways important for vascular homeostasis. Endothelial Abl deletion in Arg-null mice led to late-stage embryonic and perinatal lethality, with mutant mice displaying focal loss of vasculature and tissue necrosis. Loss of Abl kinases led to increased endothelial cell apoptosis both in vitro and in vivo, contributing to vascular dysfunction, infarction, and tissue damage. Mechanistically, we identify a unique dual role for Abl kinases in the regulation of angiopoietin/Tie2 protein kinase signaling. Endothelial Abl kinases modulate Tie2 expression and angiopoietin-1-mediated endothelial cell survival. These findings reveal a critical requirement for the Abl kinases in vascular development and function, which may have important implications for the clinical use of Abl kinase inhibitors.
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Chislock
authors.forename: Colleen
authors.initials: C
authors.lastname: Ring
authors.forename: Ann Marie
authors.initials: AM
authors.lastname: Pendergast
mesh_terms: D042683:Angiopoietin-1 / Q000502:physiology*; D017209:Apoptosis; D001808:Blood Vessels / Q000502:physiology*; D006332:Cardiomegaly / Q000235:genetics; D002470:Cell Survival / Q000502:physiology*; D005804:Genes, Lethal; D006801:Humans; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011658:Pulmonary Fibrosis / Q000235:genetics; D042787:Receptor, TIE-2 / Q000502:physiology*; D015398:Signal Transduction; D013927:Thrombosis / Q000235:genetics
chemical_list: D042683:Angiopoietin-1; D011505:Protein-Tyrosine Kinases; D042787:Receptor, TIE-2
keywords: Abl tyrosine kinases; fibrosis; heart defects; thrombosis