Increased cell stiffness contributes to complement-mediated injury of choroidal endothelial cells in a monkey model of early age-related macular degeneration.
Rac
Rho
actin
age-related macular degeneration
choroid
complement activation
endothelial cells
mechanotransduction
stiffness
Journal
The Journal of pathology
ISSN: 1096-9896
Titre abrégé: J Pathol
Pays: England
ID NLM: 0204634
Informations de publication
Date de publication:
07 2022
07 2022
Historique:
revised:
03
02
2022
received:
06
10
2021
accepted:
01
03
2022
pubmed:
4
3
2022
medline:
7
6
2022
entrez:
3
3
2022
Statut:
ppublish
Résumé
Age-related macular degeneration (AMD) is the leading cause of blindness in the aging population. Yet no therapies exist for ~85% of all AMD patients who have the dry form that is marked by degeneration of the retinal pigmented epithelium (RPE) and underlying choroidal vasculature. As the choroidal vessels are crucial for RPE development and maintenance, understanding how they degenerate may lead to effective therapies for dry AMD. One likely causative factor for choroidal vascular loss is the cytolytic membrane attack complex (MAC) of the complement pathway that is abundant on choroidal vessels of humans with early dry AMD. To examine this possibility, we studied the effect of complement activation on choroidal endothelial cells (ECs) isolated from a rhesus monkey model of early AMD that, we report, exhibits MAC deposition and choriocapillaris endothelial loss similar to that seen in human early AMD. Treatment of choroidal ECs from AMD eyes with complement-competent normal human serum caused extensive actin cytoskeletal injury that was significantly less pronounced in choroidal ECs from young normal monkey eyes. We further show that ECs from AMD eyes are significantly stiffer than their younger counterparts and exhibit peripheral actin organization that is distinct from the longitudinal stress fibers in young ECs. Finally, these differences in complement susceptibility and mechanostructural properties were found to be regulated by the differential activity of the small GTPases Rac and Rho, because Rac inhibition in AMD cells led to simultaneous reduction in stiffness and complement susceptibility, while Rho inhibition in young cells exacerbated complement injury. Thus, by identifying cell stiffness and cytoskeletal regulators Rac and Rho as important determinants of complement susceptibility, the current findings offer a new mechanistic insight into choroidal vascular loss in early AMD that warrants further investigation for assessment of translational potential. © 2022 The Pathological Society of Great Britain and Ireland.
Identifiants
pubmed: 35239183
doi: 10.1002/path.5892
pmc: PMC9337711
mid: NIHMS1785718
doi:
Substances chimiques
Actins
0
Complement Membrane Attack Complex
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
314-326Subventions
Organisme : NIH HHS
ID : P51 OD011092
Pays : United States
Organisme : NEI NIH HHS
ID : R01 EY028141
Pays : United States
Organisme : NEI NIH HHS
ID : P30 EY010572
Pays : United States
Organisme : NCRR NIH HHS
ID : S10 RR024585
Pays : United States
Informations de copyright
© 2022 The Pathological Society of Great Britain and Ireland.
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