title: VEGF regulates local inhibitory complement proteins in the eye and kidney.
abstract: Outer retinal and renal glomerular functions rely on specialized vasculature maintained by VEGF that is produced by neighboring epithelial cells, the retinal pigment epithelium (RPE) and podocytes, respectively. Dysregulation of RPE- and podocyte-derived VEGF is associated with neovascularization in wet age-related macular degeneration (ARMD), choriocapillaris degeneration, and glomerular thrombotic microangiopathy (TMA). Since complement activation and genetic variants in inhibitory complement factor H (CFH) are also features of both ARMD and TMA, we hypothesized that VEGF and CFH interact. Here, we demonstrated that VEGF inhibition decreases local CFH and other complement regulators in the eye and kidney through reduced VEGFR2/PKC-α/CREB signaling. Patient podocytes and RPE cells carrying disease-associated CFH genetic variants had more alternative complement pathway deposits than controls. These deposits were increased by VEGF antagonism, a common wet ARMD treatment, suggesting that VEGF inhibition could reduce cellular complement regulatory capacity. VEGF antagonism also increased markers of endothelial cell activation, which was partially reduced by genetic complement inhibition. Together, these results suggest that VEGF protects the retinal and glomerular microvasculature, not only through VEGFR2-mediated vasculotrophism, but also through modulation of local complement proteins that could protect against complement-mediated damage. Though further study is warranted, these findings could be relevant for patients receiving VEGF antagonists.
authors.forename: Lindsay S
authors.initials: LS
authors.lastname: Keir
authors.forename: Rachel
authors.initials: R
authors.lastname: Firth
authors.forename: Lyndsey
authors.initials: L
authors.lastname: Aponik
authors.forename: Daniel
authors.initials: D
authors.lastname: Feitelberg
authors.forename: Susumu
authors.initials: S
authors.lastname: Sakimoto
authors.forename: Edith
authors.initials: E
authors.lastname: Aguilar
authors.forename: Gavin I
authors.initials: GI
authors.lastname: Welsh
authors.forename: Anna
authors.initials: A
authors.lastname: Richards
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Usui
authors.forename: Simon C
authors.initials: SC
authors.lastname: Satchell
authors.forename: Valeryia
authors.initials: V
authors.lastname: Kuzmuk
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Coward
authors.forename: Jonathan
authors.initials: J
authors.lastname: Goult
authors.forename: Katherine R
authors.initials: KR
authors.lastname: Bull
authors.forename: Ruchi
authors.initials: R
authors.lastname: Sharma
authors.forename: Kapil
authors.initials: K
authors.lastname: Bharti
authors.forename: Peter D
authors.initials: PD
authors.lastname: Westenskow
authors.forename: Iacovos P
authors.initials: IP
authors.lastname: Michael
authors.forename: Moin A
authors.initials: MA
authors.lastname: Saleem
authors.forename: Martin
authors.initials: M
authors.lastname: Friedlander
mesh_terms: D000368:Aged; D000818:Animals; D017242:Complement Factor H / Q000235:genetics / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D005136:Eye Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D007674:Kidney Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008268:Macular Degeneration / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D050199:Podocytes / Q000378:metabolism* / Q000473:pathology; D051571:Protein Kinase C-alpha / Q000235:genetics / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000378:metabolism* / Q000473:pathology; D057049:Thrombotic Microangiopathies / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism
chemical_list: C115163:CREB1 protein, human; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D005136:Eye Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D017242:Complement Factor H; C000588866:KDR protein, human; C000592875:Kdr protein, mouse; D040301:Vascular Endothelial Growth Factor Receptor-2; C496628:PRKCA protein, human; C496630:Prkca protein, mouse; D051571:Protein Kinase C-alpha