title: Endoglin regulates the activation and quiescence of endothelium by participating in canonical and non-canonical TGF-β signaling pathways.
abstract: Endoglin (Eng) is an auxiliary receptor for transforming growth factor-β (TGFβ), with important roles in vascular function. TGFβ regulates angiogenesis through balancing the pro-proliferative and pro-differentiation signaling pathways of endothelial cells (EC). However, the contribution of endoglin to these TGFβ activities, and more specifically modulation of EC phenotype, remains elusive. Mutations in endoglin cause hereditary hemorrhagic telangiectasia-1 in humans. The Eng+/- mice are viable and exhibit some of the vascular defects seen in humans with endoglin haploinsufficiency. In the present study we show that haploinsufficiency of endoglin results in attenuation of retinal neovascularization during oxygen-induced ischemic retinopathy. Although the importance of endoglin expression in angiogenesis and vascular development has been demonstrated, the underlying mechanisms remain obscure. To gain detailed insight into the cell autonomous regulatory mechanisms that affect angiogenic properties of EC, we prepared retinal EC from Eng+/+ and Eng+/- Immorto mice. The Eng+/- EC were more adherent, less migratory, and failed to undergo capillary morphogenesis. Aortic sprouting angiogenesis was similarly attenuated in aortas from Eng+/- mice. In addition, Eng+/- EC expressed increased levels of VEGF but reduced expression of endothelial NO synthase and NO production. Mechanistically, these changes were consistent with sustained activation of mitogen-activated protein kinase (MAPK) pathways, and aberrant Smad-dependent signaling pathways in Eng+/- EC. Taken together, our results underscore the importance of endoglin in both canonical and non-canonical TGFβ signaling pathways modulating both the activation and quiescence of the endothelium during angiogenesis.
authors: Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, 600 Highland Avenue, K6/456 CSC, Madison, WI 53792-4673, USA.
authors: Sunyoung
authors: S
authors: Park
authors: Terri A
authors: TA
authors: Dimaio
authors: Wei
authors: W
authors: Liu
authors: Shoujian
authors: S
authors: Wang
authors: Christine M
authors: CM
authors: Sorenson
authors: Nader
authors: N
authors: Sheibani
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D000071063:Endoglin; D004730:Endothelium, Vascular / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008817:Mice, Mutant Strains; D018919:Neovascularization, Physiologic / Q000235:genetics*; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D051785:Smad Proteins / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D000071063:Endoglin; C502004:Eng protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; D019001:Nitric Oxide Synthase; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Angiogenesis; Endothelial cells; Extracellular matrix; MAP kinase pathways; Thrombospondins