title: Rasip1 is essential to blood vessel stability and angiogenic blood vessel growth.
abstract: Cardiovascular function depends on patent, continuous and stable blood vessel formation by endothelial cells (ECs). Blood vessel development initiates by vasculogenesis, as ECs coalesce into linear aggregates and organize to form central lumens that allow blood flow. Molecular mechanisms underlying in vivo vascular 'tubulogenesis' are only beginning to be unraveled. We previously showed that the GTPase-interacting protein called Rasip1 is required for the formation of continuous vascular lumens in the early embryo. Rasip1(-/-) ECs exhibit loss of proper cell polarity and cell shape, disrupted localization of EC-EC junctions and defects in adhesion of ECs to extracellular matrix. In vitro studies showed that Rasip1 depletion in cultured ECs blocked tubulogenesis. Whether Rasip1 is required in blood vessels after their initial formation remained unclear. Here, we show that Rasip1 is essential for vessel formation and maintenance in the embryo, but not in quiescent adult vessels. Rasip1 is also required for angiogenesis in three models of blood vessel growth: in vitro matrix invasion, retinal blood vessel growth and directed in vivo angiogenesis assays. Rasip1 is thus necessary in growing embryonic blood vessels, postnatal angiogenic sprouting and remodeling, but is dispensable for maintenance of established blood vessels, making it a potential anti-angiogenic therapeutic target.
authors.affiliation: Department of Molecular Biology and Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., NA8.300, Dallas, TX, 75390, USA.
authors.forename: Yeon
authors.initials: Y
authors.lastname: Koo
authors.affiliation: Department of Molecular Biology and Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., NA8.300, Dallas, TX, 75390, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Barry
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, 7 Divinity Ave, Cambridge, MA, 02138, USA.
authors.forename: Ke
authors.initials: K
authors.lastname: Xu
authors.affiliation: Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390, USA.
authors.forename: Keiji
authors.initials: K
authors.lastname: Tanigaki
authors.affiliation: Department of Medical Pharmacology and Physiology, University of Missouri, MA 415 Medical Sciences Building, Columbia, MO, 65212, USA.
authors.forename: George E
authors.initials: GE
authors.lastname: Davis
authors.affiliation: Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390, USA.
authors.forename: Chieko
authors.initials: C
authors.lastname: Mineo
authors.affiliation: Department of Molecular Biology and Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., NA8.300, Dallas, TX, 75390, USA. ondine.cleaver@utsouthwestern.edu.
authors.forename: Ondine
authors.initials: O
authors.lastname: Cleaver
mesh_terms: D000375:Aging / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000254:growth & development; D002352:Carrier Proteins / Q000378:metabolism*; D005260:Female; D017353:Gene Deletion; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D019426:Integrases / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D018919:Neovascularization, Physiologic; D011247:Pregnancy; D012171:Retinal Vessels / Q000196:embryology* / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; C541054:Rasip1 protein, mouse; C045073:Cre recombinase; D019426:Integrases
keywords: Angiogenesis; Blood vessel; Endothelial; Lumen; Rasip1; Tubulogenesis; VE-cadherin; Vascular; Vasculogenesis