Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Dev Cell
2011 Apr 19;204:526-39. doi: 10.1016/j.devcel.2011.02.010.
Show Gene links
Show Anatomy links
Blood vessel tubulogenesis requires Rasip1 regulation of GTPase signaling.
Xu K
,
Sacharidou A
,
Fu S
,
Chong DC
,
Skaug B
,
Chen ZJ
,
Davis GE
,
Cleaver O
.
???displayArticle.abstract???
Cardiovascular function depends on patent blood vessel formation by endothelial cells (ECs). However, the mechanisms underlying vascular "tubulogenesis" are only beginning to be unraveled. We show that endothelial tubulogenesis requires the Ras interacting protein 1, Rasip1, and its binding partner, the RhoGAPArhgap29. Mice lacking Rasip1 fail to form patent lumens in all blood vessels, including the early endocardial tube. Rasipl null angioblasts fail to properly localize the polarity determinant Par3 and display defective cell polarity, resulting in mislocalized junctional complexes and loss of adhesion to extracellular matrix (ECM). Similarly, depletion of either Rasip1 or Arhgap29 in cultured ECs blocks in vitro lumen formation, fundamentally alters the cytoskeleton, and reduces integrin-dependent adhesion to ECM. These defects result from increased RhoA/ROCK/myosin II activity and blockade of Cdc42 and Rac1 signaling. This study identifies Rasip1 as a unique, endothelial-specific regulator of Rho GTPase signaling, which is essential for blood vessel morphogenesis.
Figure 1. Rasip1 Is Essential for Vascular Tubulogenesis in All Blood Vessels
(A�D) Rasip1 expression is conserved in the embryonic vasculature across species shown by in situ hybridization: mouse (A, E9.5; B, E8.5 transverse section, left
dorsal aorta), Xenopus tropicalis (C, st.30), and zebrafish (D, 24 hpf).
(E�H) E9.5 littermate mouse embryos showing defects in Rasip1 / embryos (F) and yolk sacs (H).
(I�L) Whole-mount Flk1-lacZ beta-galactosidase staining of Rasip1+/ (I and K) and Rasip1 / (J and L) yolk sacs (I and J) and embryonic heads (K and L), showing
narrow Rasip1 / blood vessels that fail to remodel.
(M�P) Connexin40 (Cx40 or Gja5) (M and N) or EphB4-lacZ (O and P) in littermate E9.5 Rasip1+/ and Rasip1 / yolk sacs (M and N) or embryos (O and P) showing
failed arterial (M and N) and venous (O and P) differentiation in Rasip1 / vessels.
(Q�Z0 ) Flk1-LacZ beta-galactosidase staining of littermate E8.5 (6 somite stage) Rasip1+/ and Rasip1 / embryos and tissues, in whole mount or section.
(Q and R) Ventral views of E8.5 embryonic paired dorsal aortae. Anterior is up. (S�V) Transverse sections of E8.5 embryos, through the trunk region, posterior to the heart. (U and V) Close-up views, showing open lumens in Rasip1+/ ;Flk1-lacZ embryos (S and U) but lumenless cords in Rasip1 / ;Flk1-lacZ embryos
(T and V). Sections through hearts of E8.5 (W and X), showing absence of a lumen in the endocardium of Rasip1 / ;Flk1-lacZ embryos (X). Yolk sacs in whole-mount
(Y and Z) or section views (Y0 and Z0 ). Vascular tubes are absent in all Rasip1 / vessels examined. Arrows, dorsal aortae; Arrowheads, yolk sac vessels. Ys,
yolk sac; Scale bars, 500 mm (A, E, F, G, and H), 250 mm (C), 200 mm (K�P), 100 mm (D, I, J, Q, R, Y, and Z), and 50 mm (B, S, T, U, V, W, X, Y, Z, Y0 , and Z0 ).
See also Figures S1 and S2.
Aird,
Phenotypic heterogeneity of the endothelium: II. Representative vascular beds.
2007, Pubmed
Aird,
Phenotypic heterogeneity of the endothelium: II. Representative vascular beds.
2007,
Pubmed
Andrew,
Morphogenesis of epithelial tubes: Insights into tube formation, elongation, and elaboration.
2010,
Pubmed
Bayless,
The Cdc42 and Rac1 GTPases are required for capillary lumen formation in three-dimensional extracellular matrices.
2002,
Pubmed
Bayless,
Microtubule depolymerization rapidly collapses capillary tube networks in vitro and angiogenic vessels in vivo through the small GTPase Rho.
2004,
Pubmed
Bazzoni,
Monoclonal antibody 9EG7 defines a novel beta 1 integrin epitope induced by soluble ligand and manganese, but inhibited by calcium.
1995,
Pubmed
Bergers,
Modes of resistance to anti-angiogenic therapy.
2008,
Pubmed
Bohnsack,
The FAKs about blood vessel assembly.
2003,
Pubmed
Broman,
Cdc42 regulates adherens junction stability and endothelial permeability by inducing alpha-catenin interaction with the vascular endothelial cadherin complex.
2006,
Pubmed
Byron,
Anti-integrin monoclonal antibodies.
2009,
Pubmed
Carlson,
Cell-autonomous requirement for beta1 integrin in endothelial cell adhesion, migration and survival during angiogenesis in mice.
2008,
Pubmed
Carmeliet,
Targeted deficiency or cytosolic truncation of the VE-cadherin gene in mice impairs VEGF-mediated endothelial survival and angiogenesis.
1999,
Pubmed
Connolly,
Rac regulates endothelial morphogenesis and capillary assembly.
2002,
Pubmed
Conti,
Nonmuscle myosin II moves in new directions.
2008,
Pubmed
Davis,
An integrin and Rho GTPase-dependent pinocytic vacuole mechanism controls capillary lumen formation in collagen and fibrin matrices.
2003,
Pubmed
Davis,
Mechanisms controlling human endothelial lumen formation and tube assembly in three-dimensional extracellular matrices.
2007,
Pubmed
Drake,
An antagonist of integrin alpha v beta 3 prevents maturation of blood vessels during embryonic neovascularization.
1995,
Pubmed
Drake,
Antibodies to beta 1-integrins cause alterations of aortic vasculogenesis, in vivo.
1992,
Pubmed
Etienne-Manneville,
Rho GTPases in cell biology.
2002,
Pubmed
Even-Ram,
Myosin IIA regulates cell motility and actomyosin-microtubule crosstalk.
2007,
Pubmed
Even-Ram,
Of mice and men: Relevance of cellular and molecular characterizations of myosin IIA to MYH9-related human disease.
2007,
Pubmed
George,
Fibronectins are essential for heart and blood vessel morphogenesis but are dispensable for initial specification of precursor cells.
1997,
Pubmed
Gomez,
Discovery and characterization of novel vascular and hematopoietic genes downstream of etsrp in zebrafish.
2009,
Pubmed
Goody,
Dynamic interactions between cells and their extracellular matrix mediate embryonic development.
2010,
Pubmed
Iruela-Arispe,
LUMENating blood vessels.
2011,
Pubmed
Iruela-Arispe,
Cellular and molecular mechanisms of vascular lumen formation.
2009,
Pubmed
Jaffe,
Cdc42 controls spindle orientation to position the apical surface during epithelial morphogenesis.
2008,
Pubmed
Jin,
Cellular and molecular analyses of vascular tube and lumen formation in zebrafish.
2005,
Pubmed
,
Xenbase
Kamei,
Endothelial tubes assemble from intracellular vacuoles in vivo.
2006,
Pubmed
Kiosses,
Rac recruits high-affinity integrin alphavbeta3 to lamellipodia in endothelial cell migration.
2001,
Pubmed
Koh,
Cdc42- and Rac1-mediated endothelial lumen formation requires Pak2, Pak4 and Par3, and PKC-dependent signaling.
2008,
Pubmed
Koh,
Formation of endothelial lumens requires a coordinated PKCepsilon-, Src-, Pak- and Raf-kinase-dependent signaling cascade downstream of Cdc42 activation.
2009,
Pubmed
Kucera,
Vascular lumen formation from a cell biological perspective.
2007,
Pubmed
Lampugnani,
CCM1 regulates vascular-lumen organization by inducing endothelial polarity.
2010,
Pubmed
le Noble,
Flow regulates arterial-venous differentiation in the chick embryo yolk sac.
2004,
Pubmed
Lenter,
A monoclonal antibody against an activation epitope on mouse integrin chain beta 1 blocks adhesion of lymphocytes to the endothelial integrin alpha 6 beta 1.
1993,
Pubmed
Lubarsky,
Tube morphogenesis: making and shaping biological tubes.
2003,
Pubmed
Matsumura,
Regulation of myosin II during cytokinesis in higher eukaryotes.
2005,
Pubmed
Mitin,
Identification and characterization of rain, a novel Ras-interacting protein with a unique subcellular localization.
2004,
Pubmed
Morgan,
Giving off mixed signals--distinct functions of alpha5beta1 and alphavbeta3 integrins in regulating cell behaviour.
2009,
Pubmed
Myagmar,
PARG1, a protein-tyrosine phosphatase-associated RhoGAP, as a putative Rap2 effector.
2005,
Pubmed
Neumann,
Identification of a heritable model of testicular germ cell tumor in the zebrafish.
2009,
Pubmed
Nobes,
Rho, rac and cdc42 GTPases: regulators of actin structures, cell adhesion and motility.
1995,
Pubmed
O'Brien,
Opinion: Building epithelial architecture: insights from three-dimensional culture models.
2002,
Pubmed
Popoff,
Multifaceted role of Rho, Rac, Cdc42 and Ras in intercellular junctions, lessons from toxins.
2009,
Pubmed
Reardon,
The emerging role of anti-angiogenic therapy for malignant glioma.
2008,
Pubmed
Rikitake,
ROCKs as therapeutic targets in cardiovascular diseases.
2005,
Pubmed
Sacharidou,
Endothelial lumen signaling complexes control 3D matrix-specific tubulogenesis through interdependent Cdc42- and MT1-MMP-mediated events.
2010,
Pubmed
Shalaby,
Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice.
1995,
Pubmed
Siemann,
Differentiation and definition of vascular-targeted therapies.
2005,
Pubmed
Straight,
Dissecting temporal and spatial control of cytokinesis with a myosin II Inhibitor.
2003,
Pubmed
Strilić,
The molecular basis of vascular lumen formation in the developing mouse aorta.
2009,
Pubmed
Suzuki,
The PAR-aPKC system: lessons in polarity.
2006,
Pubmed
Tanjore,
Beta1 integrin expression on endothelial cells is required for angiogenesis but not for vasculogenesis.
2008,
Pubmed
Tomar,
Focal adhesion kinase: switching between GAPs and GEFs in the regulation of cell motility.
2009,
Pubmed
Villasenor,
Biphasic Ngn3 expression in the developing pancreas.
2008,
Pubmed
,
Xenbase
Wang,
Molecular distinction and angiogenic interaction between embryonic arteries and veins revealed by ephrin-B2 and its receptor Eph-B4.
1998,
Pubmed
Xu,
A ubiquitin replacement strategy in human cells reveals distinct mechanisms of IKK activation by TNFalpha and IL-1beta.
2009,
Pubmed
Xu,
Rasip1 is required for endothelial cell motility, angiogenesis and vessel formation.
2009,
Pubmed
,
Xenbase
Zaidel-Bar,
A paxillin tyrosine phosphorylation switch regulates the assembly and form of cell-matrix adhesions.
2007,
Pubmed
Zovein,
Beta1 integrin establishes endothelial cell polarity and arteriolar lumen formation via a Par3-dependent mechanism.
2010,
Pubmed
