title: Integrin-α5β1 is not required for mural cell functions during development of blood vessels but is required for lymphatic-blood vessel separation and lymphovenous valve formation.
abstract: Integrin α5β1 is essential for vascular development but it remains unclear precisely where and how it functions. Here, we report that deletion of the gene encoding the integrin-α5 subunit (Itga5) using the Pdgfrb-Cre transgenic mouse line, leads to oedema, haemorrhage and increased levels of embryonic lethality. Unexpectedly, these defects were not caused by loss of α5 from Pdgfrb-Cre expressing mural cells (pericytes and vascular smooth muscle cells), which wrap around the endothelium and stabilise blood vessels, nor by defects in the heart or great vessels, but were due to abnormal development of the lymphatic vasculature. Reminiscent of the pathologies seen in the human lymphatic malformation, fetal cystic hygroma, α5 mutants display defects both in the separation of their blood and lymphatic vasculature and in the formation of the lymphovenous valves. As a consequence, α5-deficient mice develop dilated, blood-filled lymphatic vessels and lymphatic capillaries that are ectopically covered with smooth muscle cells. Analysis of the expression of Pdgfrb during lymphatic development suggests that these defects probably arise from loss of α5β1 integrin in subsets of specialised Prox1(+)Pdgfrb(+) venous endothelial cells that are essential for the separation of the jugular lymph sac from the cardinal vein and formation of the lymphovenous valve leaflets.
authors.affiliation: Howard Hughes Medical Institute, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Turner
authors.affiliation: Howard Hughes Medical Institute, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Kwabena
authors.initials: K
authors.lastname: Badu-Nkansah
authors.affiliation: Howard Hughes Medical Institute, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Denise
authors.initials: D
authors.lastname: Crowley
authors.affiliation: Howard Hughes Medical Institute, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Arjan
authors.initials: A
authors.lastname: van der Flier
authors.affiliation: Howard Hughes Medical Institute, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address: rohynes@mit.edu.
authors.forename: Richard O
authors.initials: RO
authors.lastname: Hynes
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000196:embryology*; D005455:Fluorescent Antibody Technique; D019426:Integrases; D039121:Integrin alpha6beta1 / Q000378:metabolism*; D042601:Lymphatic Vessels / Q000196:embryology* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000502:physiology*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics; D055422:Venous Valves / Q000254:growth & development / Q000378:metabolism; D055114:X-Ray Microtomography
chemical_list: D039121:Integrin alpha6beta1; D020797:Receptor, Platelet-Derived Growth Factor beta; C045073:Cre recombinase; D019426:Integrases
keywords: Integrin; Lymphatic vessels; Mural cells; PDGFRβ