Anti-angiogenic properties of rapamycin on human retinal pericytes in an in vitro model of neovascular AMD via inhibition of the mTOR pathway.
Angiogenesis Inhibitors
/ pharmacology
Choroidal Neovascularization
/ drug therapy
Endothelial Cells
/ metabolism
Humans
Pericytes
/ metabolism
Sirolimus
/ pharmacology
TOR Serine-Threonine Kinases
/ metabolism
Vascular Endothelial Growth Factor A
Visual Acuity
Wet Macular Degeneration
/ drug therapy
Age related macular degeneration
Choroidal neovascularization
PDGF
Rapamycin
Sirolimus
VEGF
mTOR
Journal
BMC ophthalmology
ISSN: 1471-2415
Titre abrégé: BMC Ophthalmol
Pays: England
ID NLM: 100967802
Informations de publication
Date de publication:
25 Mar 2022
25 Mar 2022
Historique:
received:
02
09
2021
accepted:
25
02
2022
entrez:
26
3
2022
pubmed:
27
3
2022
medline:
31
3
2022
Statut:
epublish
Résumé
Choroidal neovascularizations (CNV) are partially stabilized through a coverage of pericytes leading to a partial anti-VEGF resistence. Drugs licensed for neovascular AMD (nAMD) do not take this mechanical and growth factor-driven CNV stability into account. The purpose of this work was to see if inhibiting the mammalian target of rapamycin (mTOR) may successfully block angiogenic cellular pathways in primary human retinal pericytes in an in vitro model of nAMD. The mTOR inhibitor rapamycin was used to treat human retinal pericytes (HRP) at doses ranging from 0.005 to 15 g/ml. A modified metabolism-based XTT-Assay was used to assess toxicity and anti-proliferative effects. A scratch wound experiment showed the effects on migration. On Cultrex basement membrane gels, the influence of rapamycin on the development of endothelial cell capillary-like structures by human umbilical vein vascular endothelial cells (HUVEC) in the absence and presence of pericytes was investigated. Rapamycin showed no signs of toxicity within its range of solubility. The drug showed dose dependent anti-proliferative activity and inhibited migration into the scratch wound. Endothelial cell tube formation in a HUVEC monoculture was effectively inhibited at 45%. A co-culture of HUVEC with pericytes on Cultrex induced endothelial tube stabilization but was disrupted by the addition of rapamycin leading to degradation of 94% of the tubes. Rapamycin allows for an efficient modulation of aspects of angiogenesis in pericytes via mTOR-modulation in vitro. Further studies are needed to elucidate whether rapamycin may have an impact on CNV in nAMD in vivo.
Identifiants
pubmed: 35337287
doi: 10.1186/s12886-022-02334-w
pii: 10.1186/s12886-022-02334-w
pmc: PMC8957126
doi:
Substances chimiques
Angiogenesis Inhibitors
0
Vascular Endothelial Growth Factor A
0
TOR Serine-Threonine Kinases
EC 2.7.11.1
Sirolimus
W36ZG6FT64
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
138Informations de copyright
© 2022. The Author(s).
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