title: Targeting endothelium-pericyte cross talk by inhibiting VEGF receptor signaling attenuates kidney microvascular rarefaction and fibrosis.
abstract: Microvascular pericytes and perivascular fibroblasts have recently been identified as the source of scar-producing myofibroblasts that appear after injury of the kidney. We show that cross talk between pericytes and endothelial cells concomitantly dictates development of fibrosis and loss of microvasculature after injury. When either platelet-derived growth factor receptor (R)-β signaling in pericytes or vascular endothelial growth factor (VEGF)R2 signaling in endothelial cells was blocked by circulating soluble receptor ectodomains, both fibrosis and capillary rarefaction were markedly attenuated during progressive kidney injury. Blockade of either receptor-mediated signaling pathway prevented pericyte differentiation and proliferation, but VEGFR2 blockade also attenuated recruitment of inflammatory macrophages throughout disease progression. Whereas injury down-regulated angiogenic VEGF164, the dys-angiogenic isomers VEGF120 and VEGF188 were up-regulated, suggesting that pericyte-myofibroblast differentiation triggers endothelial loss by a switch in secretion of VEGF isomers. These findings link fibrogenesis inextricably with microvascular rarefaction for the first time, add new significance to fibrogenesis, and identify novel therapeutic targets.
authors.affiliation: Renal Division, Department of Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Shuei-Liong
authors.initials: SL
authors.lastname: Lin
authors.forename: Fan-Chi
authors.initials: FC
authors.lastname: Chang
authors.forename: Claudia
authors.initials: C
authors.lastname: Schrimpf
authors.forename: Yi-Ting
authors.initials: YT
authors.lastname: Chen
authors.forename: Ching-Fang
authors.initials: CF
authors.lastname: Wu
authors.forename: Vin-Cent
authors.initials: VC
authors.lastname: Wu
authors.forename: Wen-Chih
authors.initials: WC
authors.lastname: Chiang
authors.forename: Frank
authors.initials: F
authors.lastname: Kuhnert
authors.forename: Calvin J
authors.initials: CJ
authors.lastname: Kuo
authors.forename: Yung-Ming
authors.initials: YM
authors.lastname: Chen
authors.forename: Kwan-Dun
authors.initials: KD
authors.lastname: Wu
authors.forename: Tun-Jun
authors.initials: TJ
authors.lastname: Tsai
authors.forename: Jeremy S
authors.initials: JS
authors.lastname: Duffield
mesh_terms: D000818:Animals; D002196:Capillaries / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology*; D005355:Fibrosis; D006801:Humans; D007113:Immunity, Innate; D007668:Kidney / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D055806:Microvessels / Q000378:metabolism / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000150:complications / Q000378:metabolism; D020286:Pericytes / Q000378:metabolism* / Q000473:pathology; D020033:Protein Isoforms / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D020033:Protein Isoforms; D042461:Vascular Endothelial Growth Factor A; D020797:Receptor, Platelet-Derived Growth Factor beta; D040301:Vascular Endothelial Growth Factor Receptor-2