title: Shear induced collateral artery growth modulated by endoglin but not by ALK1.
abstract: Transforming growth factor-beta (TGF-β) stimulates both ischaemia induced angiogenesis and shear stress induced arteriogenesis by signalling through different receptors. How these receptors are involved in both these processes of blood flow recovery is not entirely clear. In this study the role of TGF-β receptors 1 and endoglin is assessed in neovascularization in mice. Unilateral femoral artery ligation was performed in mice heterozygous for either endoglin or ALK1 and in littermate controls. Compared with littermate controls, blood flow recovery, monitored by laser Doppler perfusion imaging, was significantly hampered by maximal 40% in endoglin heterozygous mice and by maximal 49% in ALK1 heterozygous mice. Collateral artery size was significantly reduced in endoglin heterozygous mice compared with controls but not in ALK1 heterozygous mice. Capillary density in ischaemic calf muscles was unaffected, but capillaries from endoglin and ALK1 heterozygous mice were significantly larger when compared with controls. To provide mechanistic evidence for the differential role of endoglin and ALK1 in shear induced or ischaemia induced neovascularization, murine endothelial cells were exposed to shear stress in vitro. This induced increased levels of endoglin mRNA but not ALK1. In this study it is demonstrated that both endoglin and ALK1 facilitate blood flow recovery. Importantly, endoglin contributes to both shear induced collateral artery growth and to ischaemia induced angiogenesis, whereas ALK1 is only involved in ischaemia induced angiogenesis.
authors.affiliation: Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Leonard
authors.initials: L
authors.lastname: Seghers
authors.forename: Margreet R
authors.initials: MR
authors.lastname: de Vries
authors.forename: Evangelia
authors.initials: E
authors.lastname: Pardali
authors.forename: Imo E
authors.initials: IE
authors.lastname: Hoefer
authors.forename: Beerend P
authors.initials: BP
authors.lastname: Hierck
authors.forename: Peter
authors.initials: P
authors.lastname: ten Dijke
authors.forename: Marie Jose
authors.initials: MJ
authors.lastname: Goumans
authors.forename: Paul H A
authors.initials: PH
authors.lastname: Quax
mesh_terms: D030201:Activin Receptors, Type I / Q000235:genetics / Q000378:metabolism*; D030301:Activin Receptors, Type II; D000818:Animals; D001158:Arteries / Q000254:growth & development*; D002196:Capillaries / Q000378:metabolism; D002417:Cattle; D002478:Cells, Cultured; D003097:Collateral Circulation; D000071063:Endoglin; D042783:Endothelial Cells / Q000378:metabolism; D006579:Heterozygote; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D007511:Ischemia / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013314:Stress, Mechanical; D013312:Stress, Physiological; D015854:Up-Regulation
chemical_list: D000071063:Endoglin; C502004:Eng protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D030201:Activin Receptors, Type I; D030301:Activin Receptors, Type II; C498931:Acvrl1 protein, mouse