title: RhoB controls coordination of adult angiogenesis and lymphangiogenesis following injury by regulating VEZF1-mediated transcription.
abstract: Mechanisms governing the distinct temporal dynamics that characterize post-natal angiogenesis and lymphangiogenesis elicited by cutaneous wounds and inflammation remain unclear. RhoB, a stress-induced small GTPase, modulates cellular responses to growth factors, genotoxic stress and neoplastic transformation. Here we show, using RhoB null mice, that loss of RhoB decreases pathological angiogenesis in the ischaemic retina and reduces angiogenesis in response to cutaneous wounding, but enhances lymphangiogenesis following both dermal wounding and inflammatory challenge. We link these unique and opposing roles of RhoB in blood versus lymphatic vasculatures to the RhoB-mediated differential regulation of sprouting and proliferation in primary human blood versus lymphatic endothelial cells. We demonstrate that nuclear RhoB-GTP controls expression of distinct gene sets in each endothelial lineage by regulating VEZF1-mediated transcription. Finally, we identify a small-molecule inhibitor of VEZF1-DNA interaction that recapitulates RhoB loss in ischaemic retinopathy. Our findings establish the first intra-endothelial molecular pathway governing the phased response of angiogenesis and lymphangiogenesis following injury.
authors.affiliation: 1] Center for Vascular Biology Research, Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA [2] ImClone Systems (a wholly owned subsidiary of Eli Lilly and Company), New York, New York 10016, USA.
authors.forename: Damien
authors.initials: D
authors.lastname: Gerald
authors.forename: Irit
authors.initials: I
authors.lastname: Adini
authors.forename: Sharon
authors.initials: S
authors.lastname: Shechter
authors.forename: Carole
authors.initials: C
authors.lastname: Perruzzi
authors.forename: Joseph
authors.initials: J
authors.lastname: Varnau
authors.forename: Benjamin
authors.initials: B
authors.lastname: Hopkins
authors.forename: Shiva
authors.initials: S
authors.lastname: Kazerounian
authors.forename: Peter
authors.initials: P
authors.lastname: Kurschat
authors.forename: Stephanie
authors.initials: S
authors.lastname: Blachon
authors.forename: Santosh
authors.initials: S
authors.lastname: Khedkar
authors.forename: Mandrita
authors.initials: M
authors.lastname: Bagchi
authors.forename: David
authors.initials: D
authors.lastname: Sherris
authors.forename: George C
authors.initials: GC
authors.lastname: Prendergast
authors.forename: Michael
authors.initials: M
authors.lastname: Klagsbrun
authors.forename: Heidi
authors.initials: H
authors.lastname: Stuhlmann
authors.forename: Alan C
authors.initials: AC
authors.lastname: Rigby
authors.forename: Janice A
authors.initials: JA
authors.lastname: Nagy
authors.forename: Laura E
authors.initials: LE
authors.lastname: Benjamin
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D019070:Cell Lineage / Q000235:genetics; D004268:DNA-Binding Proteins; D042783:Endothelial Cells / Q000473:pathology / Q000502:physiology; D005260:Female; D005786:Gene Expression Regulation; D007249:Inflammation / Q000235:genetics / Q000503:physiopathology; D051741:Kruppel-Like Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D042583:Lymphangiogenesis / Q000235:genetics; D008297:Male; D051379:Mice; D009389:Neovascularization, Pathologic / Q000235:genetics; D012164:Retinal Diseases / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D014157:Transcription Factors; D014945:Wound Healing / Q000235:genetics / Q000502:physiology; D020743:rhoB GTP-Binding Protein / Q000235:genetics / Q000502:physiology*
chemical_list: D004268:DNA-Binding Proteins; D051741:Kruppel-Like Transcription Factors; D014157:Transcription Factors; C117684:Vezf1 protein, mouse; D020743:rhoB GTP-Binding Protein